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COLLECTED PAPERS 

of 

THE MAYO CLINIC 

Rochester, Minnesota 



EDITED BY 

Mrs. M. H. MELLISH 



VOLUME XI 
1919 

PUBLISHED SEPTEMBER, 1920 



PHILADELPHIA AND LONDON 

W. B. SAUNDERS COMPANY 

1920 



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Copyright, 1920, by W. B. Saunders Company 



PRINTED IN AMERICA 



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LIST OF CONTRIBUTORS 



Adsox, A. W., B.S., M.D., M.A., M.S. in Surgery, Chief of Section 
of Neurology in Division of Surgery.* 

Ashby, Winifred ML, B.S., M.S., Fellow in Imnrunology.t 

Balfour, D. C, M.D., F.A.C.S., Chief of Section in Division of Surg- 
ery.* Associate Professor of Surgery. f 

Barlow, R. A., B.S., M.D., Associate in Section of Oto-Laryngology in 
Division of Surgery.* Instructor in Rhinology and Oto-Laryn- 
gology. t 

Benedict, W. L., M.D., Chief of Section of Ophthalmology in Division 
of Surgery.* Assistant Professor of Ophthalmology.! 

Braasch, W. F., B.S., M.D., Chief of Section of Urology.* Profes- 
sor of Urology, f 

Brehmer, Helen E., Statistical x\ssistantin Section of Dermatology 
and Syphilology in Division of Medicine.* 

Broders, A. C, M.D., Associate in Section of Division of Pathology.* 

Bumpus, H. C, M.D., Assistant in Section of Urology.* Fellow in 
Urology, f 

Carman, R. D., M.D., Chief of Section of Roentgenology in Division 
of Medicine.* Professor of Roentgenology.! 

Clark, C. M., M.D., Assistant in Section of Laryngology, Oral and 
Plastic Surgery in Division of Surgery.* Fellow. f 

Corker y, J. R., M.D., Scholar. f 

Crenshaw, J. L., M.D., Associate in Section of Urology.* Instructor 
in Urology, f 

Eusterman, G. B., M.D., Chief of Section in Division of Medicine.* 
Assistant Professor in Medicine, f 

Evans, N., B.S., M.D., Scholar in Pathology. f 

Gardner, B. S., D.D.S., Chief of Section of Dental Surgery in Division 
of Surgery.* Assistant Professor of Dental Surgery. t 

Giffin, H. Z., B.S., M.D., Chief of Section in Division of Medicine.* 
Associate Professor of Medicine, t 

Goeckermann, W. H., M.D., Assistant in Section of Dermatology 
and Syphilology in Division of Medicine.* 

Hedblom, C. A., M.A., M.D., Chief of Section of Thoracic Surgery 
in Division of Surgery.* Fellow in Surgery. t 

Henderson, ML S., M.B., M.D. (Tor.), F.A.C.S., Chief of Section of 
Orthopaedic Surgery in Division of Surgery.* Associate Pro- 
fessor of Orthopaedic Surgery. f 

Horgan, E. J., M.D., M.S. in Surgery, Assistant in Section in Division 
of Surgery.* Fellow in Surgery. f 

*In the Mayo Clinic. 

fOnthe Mayo Foundation for Medical Education and Research, Graduate School, 
University of Minnesota. 



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IV LIST OF CONTRIBUTORS 

Judd, E. S., M.D., F.A.C.S., Chief of Section in.Division of Surgery.* 
Associate Professor of Surgery, f 

Kawamura, K., M.D., Professor of Surgery, Imperial University of 
Kyota, Kyota, Japan. Scholar, t 

Kendall, E. C., B.S., A.M., Ph.D., Chief of Section of Biochemistry 
in Division of Pathology.* Associate Professor of Biochemistry, f 

Lemon, W. S., M.B. (Tor.), Chief of Section in Division of Medicine.* 
Instructor in Medicine, f 

Lillie, H. I., B.A., M.D., Chief of Section of Oto-Laryngology in 
Division of Surgery.* Assistant Professor of Oto-Laryngology. f 

Little, G. G., M.E., Instrument maker.* 

Luden, Georgine, B.A., M.A., Arzt., M.D. (Munich), Fellow in 
Pathology, f 

Lyons, H. R., M.D., Assistant in Section of Oto-Laryngology in Divi- 
sion of Surgery.* Fellow in Oto-Laryngology. f 

MacCarty, W. C, B.S., M.D., M.S., Chief of Section in Division of 
Pathology.* Associate Professor of Pathology. t 

Magoun, J. A. H„ Jr., A.B., M.D., Fellow in Surgery.f 

Mahle, A. E., B.S., M.D., Assistant in Section in Division of Path- 
ology.* Fellow in Pathology, t 

Mann, F. C, A.B., A.M., M.D., Chief of Division of Experimental 
Surgery and Pathology.* Associate Professor of Experimental 
Surgery and Pathology, f 

Masson, J. C, M.D., F.A.C.S., Chief of Section in Division of Surgery.* 
Assistant Professor of Surgery.f 

Mayo, C. H., A.M., M.D., D.Sc, LL.D., F.A.C.S., Director of Di- 
vision of Surgery.* Professor of Surgery.f 

Mayo, W. J., A.M., M.D., D.Sc, LL.D., F.R.C.S., F.A.C.S., Director 
of Division of Surgery.* 

Meyerding, H. W., B.S., M.D., F.A.C.S., M.S. in Orthopaedic 
Surgery, Associate in Section of Orthopaedic Surgery in Division 
of Surgery.* Instructor in Orthopaedic Surgery.f 

Moore, A. B., M.D., Associate in Section of Roentgenology in Di- 

| vision of Medicine.* Assistant Professor of Roentgenology. f 

New, G. B., D.D.S., M.B., M.D. (Tor.), Chief of Section of Laryn- 
gology, Oral and Plastic Surgery in Division of Surgery.* As- 
sistant Professor of Rhinology, Laryngology, and Stomatology, f 

Osterberg, A. E., B.S., Assistant in Section of Biochemistry in Di- 
vision of Pathology.* Fellow in Biochemistry. f 

Pembertox, J. deJ., A.B., M.D., F.A.C.S., M.S. in Surgery, Chief 
of Section in Division of Surgery.* Instructor of Surgery.f 

Plummer, \V. A., M.D., Chief of Section in Division of Medicine.* 

Reeves, T. B., B.S., M.D., M.S., in Surgery, Assistant in Section 
in Division of Surgery.* Fellow in Surgery.f 

Richards, C. G., M.D., Scholar in Urology. f 

Rosenow, E. C, M.D., Chief of Division of Experimental Bacteri- 
ology.* Professor of Experimental Bacteriology . f 

* In the Mayo Clinic. 

fOn the Mayo Foundation for Medical Education and Research, Graduate School, 
University of Minnesota. 



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LIST OF CONTRIBUTORS V 

Saxdiford, Irene, A. B., Ph.D. Associate in Section of Clinical 
Metabolism in Division of Medicine.* Fellow in Medicine. t 

Saxford, A. H., A.B., A.M., M.D., Chief of Section of Clinical Labo- 
ratories in Division of Medicine.* Associate Professor of Clin- 
ical Bacteriology and Parasitology.! 

Sistrunk, W. E., M.D., F.A.C.S., Chief of Section in Division of 
Surgery.* Associate Professor of Surgery, f 

Stokes, J. H., A.B., M.D., Chief of Section of Dermatology and Syphil- 
ology in Division of Medicine.* Associate Professor of Medicine, f 

Sturdivant, B. F., Assistant in Division of Experimental Bacteri- 
ology.* 

Weld, E. H., A.B., M.D., M.S. in Surgery, Fellow in Surgery, f 

Willius, F. A., B.S., M.D., Associate in Section of Division of Medi- 
cine.* Fellow in Medicine, f 

Wilson, L. B., M.D., Director of Division of Pathology, Director of 
The Mayo Foundation. Professor of Pathology. f 

Woltman, H. W., B.S., M.D., Ph.D. in Neurology, Associate in 
Section of Neurology in Division of Medicine.* Instructor in 
Medicine, f 

Mrs. M. H. Mellish, Editor 



* In the Mayo Clinic. 

t On the Mayo Foundation for Medical Education and Research, Graduate School, 
L'niversity of Minnesota. 



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CONTENTS 

Alimentary Canal 

Page 
A Study of the Arteries Supplying the Stomach and Duodenum and their 

Relation to Ulcer 3 

Angioma of the Stomach 23 

The Operabiuty of Cancer of the Stomach as Determined by the AT-ray 30 

Cancer of the Stomach and Its Surgical Treatment 41 

Diagnosis of Late Recurrences Following G astro- enterostomy: A Prelim- 
inary Report on 84 Cases of Gastrojejunal Ulcer 52 

An Experimental Study of the Effects of Duodenectomy 63 

The Routine Management of Duodenal Ulcer Cases 70 

Surgical Treatment in the Bleeding Type of Gastric and Duodenal Ulcer . 80 
Life Expectancy of Patients Following Operations for Gastric and 

Duodenal Ulcer 93 

A Comparative Study of the Anatomy of the Sphincter at the Duodenal 
End of the Common Bile Duct With Special Reference to Species of 

Animals Without a Gallbladder 98 

A Study of the Tonicity of the Sphincter at the Duodenal End of the 

Common Bile Duct 104 

Early Lesions in the Gallbladder 108 

Jaundice and Its Surgical Significance 116 

The Histogenesis of Carcinoma in the Islets of the Pancreas 124 

The Utility of the Rubber Tube in Intestinal Surgery 146 

Urogenital Organs 

Toxicity of Pyelography Mediums: Report of a Death Following the 

Use of Thorium Nitrate 165 

The Pelvis of the Kidney as a Possible Source for Infection of the Blood 

Stream: A Preliminary Report 177 

Hematogenous Infections of the Kidney 183 

Recent Advance in the Diagnosis of Surgical Lesions of the Kidney 192 

Renal Fluoroscopy at the Operating Table 203 

Surgical Renal Tuberculosis: The Prognosis 207 

Papillary Tumors of the Pelvis of the Kidney 221 

Surgery of the Kidney 236 

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Vlll CONTENTS 

Page 

Dilatation of the Ureter and Renal Pelvis 248 

Conditions Contra-indicating Operation With Stone in the Kidney and 

Ureter 262 

Stone in the Kidney 268 

The Results of Operations for the Removal of Stones from the Ureter 276 

Surgery of the Urinary Bladder 291 

Secondary Melano-Epithelioma of the Bladder 298 

Diverticula of the Posterior Urethra 800 

The Treatment of Urethral Caruncle 308 

Diseases and Treatment of the Prostate Gland 316 

The Operative Treatment of Vesicovaginal Fistula 322 

Ectopic Adenomyoma of Uterine Type (A Report of Ten Cases) 335 

Malignant Myomas and Related Tumors of the Uterus 349 

Studies on Organ Transplantation 376 

I. Transplantation of the Thyroid Gland With Intact Blood Supply . . 376 

Isolation of the Iodin Compound Which Occurs in the Thyroid 396 

The Physiologic Action of Thyroxin 417 

The Chemical Identification of Thyroxin 424 

The Basal Metabolic Rate in Exophthalmic Goiter With A Brief Descrip- 
tion of the Technic Used at the Mayo Clinic 489 

Tuberculosis of the Thyroid 504 

The Selection of Operation for Exophthalmic Goiter 510 

Tetany in the Eunuchoid. Report of a Case 516 

The Effect of Splenectomy on the Thymus 534 

Heart 

Auricular Fibrillation and Life Expectancy 543 

Observations on Chancjes in Form of the Initial Ventricilar Complex in 

Isolated Derivations of the Human Electrocardiogram 565 

Blood 

Studies on Organ Transplantation 587 

Transplantation of the Spleen With Intact Blood Supply 587 

Studies on Cholesterol 598 

VI. The Value of Blood Cholesterol Determinations and their 

Place in Cancer Research 598 

The Determination of the Length of Life of Transfused Blood Corpuscles 

in Man 621 

Practical Considerations of the Dangers Associated With Blood Trans- 
fusions 635 



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CONTENTS IX 

P.VOE 

Diagnostic Methods in the Anemias 641 

The Results op Splenectomy in the Anemias 653 

Persistent Eosinophilia With Hyperleukocytosis and Splenomegaly 662 

Skin and Syphilis 

Basal-cell Epithelioma 677 

Congenital Ectodermal Defect With Report op a Case 693 

Syphilis in Railroad Employees 711 

The Need of Hospital Beds for Syphilis 726 

Head, Trunk and Extremities 

The Treatment of Tuberculosis of the Spine 735 

Intracapsular Extraction of Cataracts 745 

The Use of Radium in the Treatment of Diseases of the Eye and Adnexa . . 754 

Treatment of Chronic Dacryocystitis , 765 

Mastoiditis, Acute and Subacute. Results in a Series of Operated Cases 774 

Rhinophyma 778 

Squamous-cell Epithelioma of the Lip: A Study of Five Hundred Thirty- 
seven Cases 783 

Ankylosis of the Jaw Due to Fixation of the Temporal Muscle 812 

Retracting and Suturing of Soft Tissues with Regard to the Extraction 

of the Lower Impacted Third Molar 817 

Studies on Elective Localization 819 

Tonsillectomy in Myositis and Arthritis 870 

Angiomas of the Larynx: Report of Three Cases 877 

Ax Unusual Malignant Tumor of the Pharynx 896 

Amyloid Tumors of the Upper Air Passages 898 

The Surgical Treatment of Cysts of the Thyroglossal Tract 914 

Studies in Influenza and Pneumonia 919 

II. The Experimental Production of Symptoms and Lesions Simu- 
lating Those of Influenza with Streptococci Isolated During 

the Present Pandemic 919 

III. The Occurrence of a Pandemic Strain of Streptococcus During 

the Pandemic of Influenza 929 

IV. Further Results of Prophylactic Inoculations 934 

Therapeutic Effects of a Monovalent Antistreptococcus Serum in 

Influenza and Influenzal Pneumonia 949 

Pulmonary Suppuration 962 

Foreign Bodies of Dental Origin in a Bronchus : Pulmonary Complications 997 

Ununited Fractures of the Hip 1017 



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X CONTENTS 

Page 

The Surgical Treatment of Bunions 1024 

Benign Xanthic Extraperiosteal Tumor of the Extremities Containing 

Foreign-Body Giant Cells 1032 

Chondromas 1054 

A Roentgenologic Study of Metastatic Malignancy of the Bones 1066 

Fractures Considered as Potential Deformities 1071 

Nerves 

Study X: The Etiology and Treatment of Acute Poliomyelitis 1085 

A Clinical Study of Nerve Anastomosis 1090 

Cutting the Sensory Root of the Gasserian Ganglion for the Relief of 

Trifacial Neuralgia 1 109 

Technic 

Exposure in Gallbladder Surgery 1 123 

An Extra Tag on the Abdominal Sponge 1128 

A Method for the Preparation of Prophylactic and Autogenous Lipo- 

vaccines 1 181 

Head Rests for Neurologic Operations 1141 

Scalpel Sharpening 1 145 

A Method for Preserving a Sharp Scalpel in Experimental Surgery 1151 

Turkish Wash Cloths for Packs in Experimental Surgery 1152 

The Use of Turpentine Resin in Turpentine as a Foam Breaker 1153 

The Use of Coal as a Substitute for Talcum to Induce Rapid Boiling 1 154 

General 

Socialization of Medicine and of Law 1157 

Presidential Address 1 166 

Educational Possibilities of the National Medical Museum 1172 

The Relation of Mouth Conditions to General Health 1180 

The Relation of Cancer to the Prolongation of Human Life 1192 

Protein Sensitization in Asthma and Hay Fever 1201 

The Organization and Methods of Contagious Disease Services 1211 

Experimental Surgical Shock 1225 

V. The Treatment of the Condition of Low Blood Pressure Which 

Follows Exposure of Abdominal Viscera 1225 

The R6le of the Pathologist in the Practice of Medicine 1243 

A Mathematical Terminology for Neoplasia and Its Significance. . . 1249 

The Pathologic Service of the American Expeditionary Forces 1262 



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CONTENTS XI 

Page 

Museum and Abt Service of the American Expeditionary Forces 1278 

Graduate Medical Education in Great Britain and France 1288 

Memorial Meeting in Honor of Sir William Osler 1293 

Index of Contributors 1299 

Bibliographic Index 1303 

Index of Subjects 131 3 



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ALIMENTARY CANAL 



19—1 



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A STUDY OF THE ARTERIES SUPPLYING THE 

STOMACH AND DUODENUM AND THEIR 

RELATION TO ULCER* 

T. B. REEVES 



This work was undertaken to determine, if possible, whether there 
is any difference in the character of the arteries in the stomach and 
duodenum, in the regions in which ulcers are prone to occur. At the 
operating table practically all ulcers of the stomach are found along 
the lesser curvature, and 98 per cent of the duodenal ulcers are found 
within one and one-half inches of the pylorus; the greater number on 
the anterior wall within the first inch. It would seem that there must 
be a special factor to cause this curiously selective character. 

The two portions of the bowel, the stomach, and the first one and 
one-half inches of the duodenum should be considered as modified 
portions of the same region of the primitive alimentary tube. From 
an embryologic standpoint the beginning of the duodenum resembles 
the stomach in that it arises from the foregut. The first inch is freely 
movable; it is covered in front and behind by the same two layers of 
peritoneum that cover the stomach. The mucous surface of the first 
one and one-half inches of the duodenum is devoid of folds (valvulse 
conniventes) and the villi are short. The distribution of blood ves- 
sels supplying the stomach and the first one and one-hal inches of 
the duodenum is not regular as it is n the rest of the bowel. 

Technic 

Sixty-two human stomachs and duodenums procured at necropsies 
from one to four hours after death have been investigated. Most of 
the specimens were injected before being removed from the body. 
For injecting the arteries, slightly acid gelatin-carmin solution gave 
the best results. Ten per cent gelatin solution was filtered through 
several thicknesses of cheese cloth. Sufficient carmin to make 1.5 
per cent solution was ground in a mortar and partially dissolved in a 
* Reprinted from Surg., Gynec. and Obst. 1920, xxx, 374-385. 

3 



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4 T. B. REEVES 

small amount of water containing a few drops of acetic ac d; this was 
added to the warm gelatin solution and thoroughly stirred. A few 
crystals of thymol were added as a preservative. When ready for use 
the gelatin-carmin was melted over a water bath and injected at a 
temperature between 45°C. and 50°C. To inject the capillaries the 
carmin should first be dissolved in ammonium hydroxid to get rid 
of the granules, then neutralized with acetic acid (Bayne-Jones). 
If the gelatin-carmin solution is alkaline, the dye will diffuse through 
the tissue and obscure smaller vessels. 




Fig. 1. — Stereoscopic roentgenogram. Vessels injected with gelatin-bismuth solution. 

All of my injections were made through the celiac axis, the hepatic 
artery being ligated at the porta hepatis, and the inferior pancreatico- 
duodenal at its origin from the superior mesenteric. In some of the 
cases the splenic artery was clamped off at the hilus of the spleen 

Several injections were made to include the capillaries but no 
attempt was made to inject the veins, although they were partially 
filled in a few instances. As a rule the best injections were in stomachs 
that were moderately distended either with air or fluid. Specimens 



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BELATION OF THE ARTERIES OF THE STOMACH TO ULCER 5 

distended with air soon after injection were useful when hardened and 
dried. Fixation of specimens in 10 per cent formalin solution for 
twelve to twenty-four hours immediately after injection proved the 
most instructive method as it was then comparatively easy to make a 
complete dissection of the vessels of the submucosa by means of a 
dissecting microscope. For microscopic study, blocks of t ssue were 
cut from various parts of the stomach and duodenum and fixed in 10 
per cent formalin. Serial frozen sections from 50 to 100 microns were 
cut, stained with hematoxylin and mounted in balsam. 

A few specimens were injected with 10 per cent gelatin to which 
was added bismuth or barium sulphate. One specimen was injected 
with 15 per cent thorium and one with 25 per cent sodium bromid. 
Each of these specimens was distended with air and sterioscopic 
roentgenograms taken. The one containing barium or bismuth made 
the best roentgenograms (Fig. 1), but since they showed only the 
larger vessels in the submucosa, they were of little value in this study. 

The Gastric Arterial System 

It may be well to describe briefly the larger vessels supplying the 
stomach and the duodenum, although my chief interest in this study 
was in the smaller vessels of the mucosa and submucosa of those areas 
of the stomach and duodenum in which ulcer is most often found. 

The Celiac Axis 

The celiac axis (arteria coeliaca) is given off from the anterior 
surface of the aorta between the crura of the diaphragm a short dis- 
tance below the aortic opening. It is a short, thick trunk, extends 
forward and slightly downward above the upper margin of the pan- 
creas for about one-half inch, and then breaks up simultaneously just 
behind the posterior layer of the lesser sac of peritoneum into the 
gastric, hepatic and splenic arteries. 

The Gastric Artery 

The gastric artery (arteria gastrica sinistra) runs upward and to 
the left, crosses the left crus of the diaphragm behind the peritoneum 
and gains the lesser curvature of the stomach near the cardiac end 
by arching forward between the two layers of peritoneum which are 
reflected from the stomach and esophagus on to the diaphragm. On 
reaching the stomach the artery gives off an esophageal branch which 



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6 



T. B. REEVES 



soon divides into several smaller ones to supply the terminal esophagus 
and a limited area of the stomach around the cardia. Just after giving 
off the esophageal branches the artery curves downward and to the 
right along the lesser curvature between the two layers of the gastro- 
hepatic omentum. It soon divides into two branches, both having 
their path along the lesser curvature, one anterior and one posterior. 




Fig. 2. — Dissection, illustrating the blood supply of the stomach and duodenum. Note 
the number of vessels along the greater curvature in comparison with the lesser. 

In their course, these branches give off from three to five branches 
to the surface of the stomach next to which they travel, as well as some 
very small branches to the lesser curvature and to the gastrohepatic 
omentum. The two main branches may terminate in several different 
ways. Both may anastomose with the two terminal branches of the 
pyloric artery (arteria gastrica dextra) which in such a case is bifur- 



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RELATION OF THE ARTERIES OF THE STOMACH TO ULCER 7 

cated, or only one, more frequently the posterior branch, will anas- 
tomose with the non-bifurcated pyloric artery (Figs. 2 and 3). In 
other cases there is no end-to-end anastomosis with the pyloric on the 
surface of the stomach; each branch is lost by the perforation of its 
secondary divisions into the muscular coats of the stomach; the anas- 
tomosis then takes place in the submucosa. Because of the absence 



Su 



p. pancreat 




Fio. 3. — Dissection showing the blood vessels and their relations to the pyloric end of 
the stomach and the duodenum. Anterior view. Pancreas dissected away. 

of the pyloric artery in a very few instances no sort of anastomosis 
can be found. Leriche and Villemin found no anastomosis in 6 of 
55 cases. In a single case of my series of 62 cases no anastomosis 
could be found; this was due to the absence of the pyloric artery. 
From the arcade along the lesser curvature there are from 3 to 5 
branches which run downward on both the anterior and posterior wall 



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8 T. B. REEVES 

for a variable distance to penetrate the muscular coats. A second 
group of very small arteries enters directly through the muscular coats 
on the lesser curvature. 

The Hepatic Artery 

The hepatic artery runs slightly forward and to the right over the 
right crus of the diaphragm and along the upper border of the head of 
the pancreas behind the posterior layer of the lesser sac of peritoneum. 
It bends forward, crosses the left surface of the portal vein, and enters 
between the two layers of the gastrohepatic omentum at the upper 
margin of the duodenum. It then courses upward and to the right 
to the porta hepatis of the liver lying in the free margin of the gastro- 
hepatic omentum in front of the portal vein and to the left side of 
the common bile duct. On entering between the two layers of the 
gastrohepatic omentum the hepatic artery gives off the pyloric artery 
(arteria gastrica dextra). This vessel descends between the two layers 
of peritoneum to the pylorus, giving off branches both to the anterior 
and posterior surfaces, which usually anastomose with the duodenal 
vessels in the submucosa. The artery terminates on the lesser 
curvature of the stomach as described. The gastroduodenal artery 
is given off from the hepatic soon after the pyloric. It varies from 
one-half to one inch in length and descends behind the first part of 
the duodenum about three-fourths of an inch to the right of the 
pylorus, where it terminates by dividing into the superior pancreatico- 
duodenal and the right gastro-epiploic. The right gastroepiploic 
usually gives off one or two very small branches to the lower margins of 
the first part of the duodenum, then enters between the two layers of 
the gastro-colic omentum to run along the greater curvature of the 
stomach and anastomoses with the left gastro-epiploic from the splenic. 
From this arch branches are given off at much more frequent inter- 
vals than on the lesser curvature. Although arteries from the lesser 
curvature are fewer in number they run a longer course (Figs. 2 and 3). 
The branches from both arches run in the serous coat for a s*hort 
distance, then perforate the muscular layers to form a very extensive 
series of anastomoses in the submucosa. 

The Splenic Artery 

The splenic artery (arteria lienalis) runs a rather tortuous course 
more or less horizontally to the left over the left crus of the diaphragm, 



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RELATION OF THE ARTERIES OF THE STOMACH TO ULCER 9 

left suprarenal and upper pole of the left kidney, and just above the 
upper margin of the pancreas behind the posterior wall of the lesser 
sac of peritoneum. On leaving the region of the kidney it enters 
between the two layers of the lienorenal ligament and breaks up into 
several branches which enter the hilus of the spleen and at the same 
time give off the right gastro-epiploic and several short gastric branches. 
These vessels enter between the two layers of the gastrolienal ligament 
and pass on to the greater curvature of the stomach. The left gastro- 
epiploic runs to the right and by anastomosing with the right gastro- 
epiploic it forms the arcade of the greater curvature. The short 
gastric branches are distributed to the left end of the greater curvature 
where they help to supply the fundus, and they pass to both anterior 
and posterior surfaces and anastomose in the submucosa with the 
cardiac branches of the left gastric and left gastro-epiploic arteries. 

Arteries of the Gastric Submucosa and Mucosa 

On examining the plexus or series of anastomoses made by the 
arteries in the submucosa it is found that there is quite a marked 
difference between those of the lesser curvature and those of the rest 
of the stomach. Compare Figures 5 and 6. 

All the arterial branches destined to supply the stomach penetrate 
the muscle coats and enter the submucosa where they form a very 
extensive plexus, or net-work of comparatively large vessels. Those 
from both curvatures anastomose freely with each other and reach 
across to anastomose with those of the opposite curvature (Fig. 4). 
The plexus is remarkable in that all the vessels run a very tortuous 
wavy course and give off branches which are to a great extent of equal 
size throughout the entire stomach except along the lesser curvature. 
Since the submucous plexus on the lesser curvature is different from 
that in other parts of the stomach, I shall describe it separately: It 
is made up by small perforating branches from the main trunks along 
the esser curvature. On entering the submucosa these vessels 
bifurcate and run more or less parallel with each other between the 
esophageal opening and the pylorus. They are much smaller, make 
fewer anastomoses and run more than twice the distance of the same 
sized vessel in any other part of the stomach (Fig. 5). By means 
of rather small branches this plexus anastomoses with those on the 
anterior and posterior walls. The two plexuses have the same relative 



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10 



T. B. REEVES 



position in the wall of the stomach, that is, midway between the 
inner muscle coat and the muscularis mucosa. In an injected speci- 




Fig. 4. — Arteries of the submuoosa of the posterior wall of the stomach. Note the 
tortuous course of the smallest branches. Dissection photograph. 

men it is quite easy to dissect away either or both the mucous and 
muscular coats. 




Fio. 5. — Dissection illustrating the submucous plexus of arteries on lesser curvature 
of stomach. Note the length, size, and general direction. 

From the plexus of arteries in the submucosa two systems of 
branches are given off; one passes to the muscular coats and the other 
to the mucous coat . I shall not describe the former. In many respects 



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RELATION OF THE ARTERIES OF THE STOMACH TO ULCER 11 



^v&C 




Fig. 6. — Arteries of stomach mucosa with a few capillaries injected. Photomicrograph 

(X 50). 




Fig. 7. — Vessels entering the gastric mucosa. Note the sudden diminution in size 
of the vessels. Many branches are not injected because of plugging with carmin 
granules. Photomicrograph ( X 50). 



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12 T. B. REEVES 

my findings agree with the investigations of Disse published in 1904. 
The system of vessels going to the mucosa is somewhat complicated. 
The vessels run in a slanting direction toward the muscularis 
mucosa and at the same time take a very tortuous course. They 
usually divide twice before reaching the muscularis, the branches 
having the same spiral-like course, often twisting about each other 
and in this manner passing through the muscularis mucosa. As 
they enter into the mucosa they suddenly become smaller by giving 
off branches that are terminal arteries, connected only by means of a 
capillary network (Figs. 6 and 7). These vessels continue to run 
a rather winding course and it seems that the transition from arterioles 
into capillaries may take place anywhere in the mucosa, but for the 
most part the change is in the deepest half. According to Disse 
each end-artery supplies an area of mucosa about 2.5 mm. in diameter. 
From the character and arrangement of the arteries in the submucosa, 
it would seem that they are markedly well adapted for the regulation 
of the blood supply to the mucosa. 

Arteries of the Duodenum 

The duodenum, except for its first one and one-half inches, receives 
its blood supply entirely from the superior and inferior pancreatico- 
duodenal arteries. The superior is one of the terminal branches of the 
gastroduodenal, and arises behind the duodenum about three-fourths 
of an inch to the right of the pylorus. It inclines to the right and soon 
divides into an anterior and posterior branch. These, however, may 
come off separately from the gastroduodenal (Fig. 8). The two 
branches run downward between the duodenum and the head of the 
pancreas; they are both overlapped by the thin margin of the pancreas 
projecting in front of and behind the margin of the duodenum. The 
posterior of these branches runs in intimate relation with the lower 
portion of the common bile duct (Figs. 3 and 8). The inferior pan- 
creaticoduodenal is given off from the superior mesenteric just before 
the latter passes in front of the third part of the duodenum. It runs 
to the right behind the superior mesenteric vein and soon divides into 
anterior and posterior branches which run along between the duo- 
denum and the pancreas to anastomose with the two branches of the 
superior pancreaticoduodenal, thus making two arcades in the curva- 
ture of the duodenum as shown in Figures 3 and 8. From these two 



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RELATION OF THE ARTERIES OF THE STOMACH TO ULCER 



13 



arcades, branches pass quite regularly to the anterior and posterior 
walls of the duodenum and tend to encircle the bowel. After reaching 
the bowel they soon pierce the muscular coats and form a submucous 
plexus by a series of anastomosing arcades (Fig. 9). This plexus is 
made up of a series of branches given off from the larger arteries 
encircling the bowel. These branches anastomose with each other; 



R. gastroepiploic A 

iTif. pan, ere 

duodenal 




icodu.o do mxl A. 

fHepatic A 

flroda ode nai A 
mon bile duct 



MJ.I^t. 



Fio. 8. — Dissection drawing showing the blood vessels and their relations to the pyloric 
end of the stomach and the duodenum. Posterior view. Pancreas dissected away. 

they are short and relatively of the same length and caliber. The 
encircling vessels become gradually smaller until finally they are 
the same size as the anastomosing branches. Under these conditions 
it seems that the blood pressure must be the same in all branches 
entering the mucosa, thus insuring a constant blood supply to all 
parts of the mucosa. From the submucous plexus vessels are given 



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14 



T. B. REEVES 



off to supply the muscular coats; these vessels will not be described 
here. The greater part of the blood stream is carried to the mucosa 




Fig. 9. — Anterior wall of the second part of the duodenum; muscular flap dissected 
away. Photograph of specimen. 









rJktfx 




Fig. 10. — Villus and crypt type of arteries in duodenum. Capillaries injected. 

Photomicrograph (X 50). 

through two sets of arteries, one to the villi, and one to the lower ends 
of the crypts. The arteries, on piercing the muscularis, give off a 



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RELATION OF THE ARTERIES OF THE STOMACH TO ULCER 



15 




Fig. 11. — Dissection photograph showing submucous plexus of arteries. First.part of 
duodenum. Note how the vessels are in the first inch. 










> 



•• • .. 



Fig. 12. — Gastric type of spiral artery in the duodenum. Branches plugged with 
eannin granules, hence no other vessels in the field. This is in itself suggestive of a 
terminal artery. Photomicrograph (X 100). 



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T. B. REEVES 



variable number of branches to the villi, there being usually one to 
each villus. This artery passes almost through the center and termi- 
nates in capillaries near the summit (Fig. 10). The crypt type of 
artery, on entering the mucosa, divides into several branches which 
radiate in all directions, and run along the bases of the glands (Mall). 
These in turn give off branches which pass upward around the glands 
and soon terminate in capillaries which supply the glands and stroma 
(Fig. 10). 




Fig. 



13. — Gastric type of spiral artery entering mucosa of duodenum. Branches 
plugged with carmin gelatin. Photomicrograph ( X 100). 



The first one and one-half inches of the duodenum receive their 
blood supply chiefly from an artery which is usually given off from the 
gastroduodenal or hepatic. This vessel has been described at length 
by Wilkie under the name of "supraduodenal artery." From its 
origin, as shown in Figures 2, 3, and 11, it runs downward between the 
two layers of the lesser omentum to the upper margin of the duodenum. 
Here it gives off a small branch to the posterior surface of the duo- 
denum while the main vessel comes on the anterior surface to anasto- 
mose rather sparingly with a small branch of the pyloric, a small 
branch of the right gastro-epiploic, and with branches of the superior 
pancreaticoduodenal (Fig. 11). The posterior wall of the first one 
and one-half inches of the duodenum is supplied chiefly by small 
branches from the gastroduodenal artery, given off as that vessel 



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RELATION OF THE ARTERIES OF THE STOMACH TO ULCER 



17 



passes behind the bowel. It also receives some small twigs from the 
supraduodenal, pyloric, and right gastro-epiploic arteries. These 
arteries, soon after reaching the wall of the duodenum, penetrate the 
muscular coat and form a submucous plexus which is strikingly 
different from that lower down in the bowel. Compare the first and 
second halves of Figure 11. The first inch certainly has very few 
arteries in the submucosa in comparison with other parts of the 
duodenum. It would seem that this explains the observation of 




Fig. 14. — Gastric type of artery in first inch of the duodenum, giving off villus 
branches. The smaller cryptic branches are plugged with injecting material. Photo- 
micrograph ( X 50). 

W. J. Mayo regarding the "anemic spot" produced by traction, 
usually seen on the surface of the bowel in this region. From the 
submucous plexus of vessels branches are given off to the mucosa 
which simulate to a marked degree the vessels of the stomach. They 
are not quite so large nor do they run so consistently tortuous a course. 
Yet many are definitely of the spiral gastric type; this is particularly 
noticeable just as they enter the muscularis mucosa (Figs. 12 and 13). 
Beside the gastric type of crypt vessels in the first inch of the duo- 
denum is the villus type; and since the villi are not so- numerous 

'19—2 



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•18 T. B. REEVES 

nor so high as they are farther down in the bowel, these arteries 
are correspondingly modified (Fig. 14). There are possibly a few 
more arteries in the submucous plexus on the posterior than on the 
anterior wall of this portion of the duodenum otherwise the blood 
vessels are similar. 

The transition from stomach to duodenum is not sharply marked 
either in the mucosa or in the submucosa. Brunner's glands are 
often found in the pylorus and the pyloric glands frequently extend 
over into the duodenum (Bailey). In fact, Brunner's glands are 
believed by Oppel and others to be a continuation of the pyloric 
glands. Certainly the gastric type of artery is carried over into 
the duodenum, the change being gradual. According to Mall, the 
crypt vessels of the small intestine become submucous vessels in the 
stomach and the arteries to the villi become smaller and are the 
stellate vessels of the mucosa in the stomach. 

The Significance of Gastric and Duodenal Arteries in Relation 

to Ulcer 

The character of the arteries of the submucosa and of the mucosa of 
the stomach from a normal as well as from a pathologic standpoint 
has a physiologic significance. The glands secrete chiefly during 
digestion when the walls of the stomach are expanded; during this 
period they need a rich blood supply. From a physiologic standpoint 
it is of advantage to the organism if the flow of blood to the capillaries 
of the mucosa is made less difficult when the stomach is filled, and that 
the blood supply is limited when the stomach is empty. With a full 
stomach, when the walls are expanded, all of the rugae or folds of the 
mucosa disappear except two along the lesser curvature; all the wind- 
ing spiral curves and marked tortuosities of the arteries are straight- 
ened out, except those along the lesser curvature; thus the resistance 
offered the blood stream by the very tortuous arteries decreases and 
the flow of blood to the mucosa is made less difficult (Waldeyer). 
Of course, there is undoubtedly a nervous influence at work at the same 
time, causing a dilatation of the vessels. But the latter influence is 
entirely separate and distinct from the mechanical resistance offered 
by the vessels. As the stomach empties itself and becomes gradually 
smaller following digestion, the arteries of the mucosa and submucosa 
become more tortuous and the blood meets with greater resistance. 



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RELATION OF THE ARTERIES OF THE STOMACH TO ULCER 19 

Thus the blood content of the mucosa is not nearly so great in an 
empty as in a full stomach. 

Among the most generally accepted theories advanced regarding 
the etiology of gastric and duodenal ulcer is the theory that they are 
caused by a hematogenous infection. The clinician and the surgeon 
in their attempts to establish a cure for ulcer are realizing more and 
more that they are dealing with an infectious process. 

Pathologic changes in the vessels result in marked changes in the 
blood flow, due not only to partial obstruction, but also to a diminished 
elasticity and contractility of the arterial walls. Virchow was among 
the first to call attention to the fact that thrombosis or other vascular 
lesions producing obstruction of the vessels in the gastric mucosa result 
in hemorrhagic necrosis which, in the presence of the gastric juice, 
leads to ulcer. A local end-arteritis producing practically an obstruc- 
tion of a vessel, which makes few or no anastomoses and supplies 
relatively a large area of the mucosa, probably causes a chronic gastric 
ulcer in rare instances in elderly persons, just as superficial ulcers and 
even gangrene are produced elsewhere by the same cause. This type 
of ulcer will not heal, probably because of the lack in power of the 
diseased vessels to regenerate new ones to supply the affected area 
with arterial blood. Various observers in their attempts to produce 
gastric and duodenal ulcer by disturbing the circulation have shown 
that embolism of the vessels entering through the muscularis mucosa 
gives the most pronounced results. The collateral circulation of the 
vessels in the submucosa is so great that one of the four large vessels 
passing on to the wall of the stomach may be ligated without caus- 
ing harm to the stomach (Baumann). The collateral criculation in 
the mucosa, however, is limited, for the most part, to capillaries. 

Cohnheim, in 1890, produced acute ulcers by the injection of foreign 
substances into the gastric circulation. In these cases the injecting 
material seemed to occlude the vessels entering the muscularis mucosa 
and to cut off the circulation to a limited area of the mucosa. The 
action of the gastric juice on the dead or devitalized tissue probably 
contributed to the production of acute ulcers. This type of ulcer 
heals readily since there is nothing to cause additional destruction 
of tissue, and since the natural tendency of the body is to repair the 
damage done. 

Rosenow injected streptococci isolated from gastric and duodenal 
ulcers in man into the venous circulation of experimental animals and 



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•20 T. B. REEVES 

produced gastric and duodenal ulcer in 60 per cent, and a total of 
ulcer and hemorrhage in 83 per cent of the animals injected. I quote 
from his summary: "The ulcers produced by the injection of strepto- 
cocci resemble those in man in location, in gross and microscopic 
appearance, and in that they tend to become chronic, to perforate, 
and to cause severe or fatal hemorrhage." According to Rosenow's 
description, "both the circumscribed hemorrhage and the ulcer are 
cone-shaped with the base of the cone at the surface and the apex at 
the muscularis." From the anatomic arrangement of the vessels in 
the mucosa, this circumscribed area of hemorrhage is just what one 
would expect from thrombosis or disturbance of the circulation of 
the vessels entering through the muscularis mucosa. Since this type 
of ulcer is produced by streptococci it tends to become chronic and to 
have all the characteristics of ulcer in man ; the streptococci serve as a 
constant irritant and prevent healing. The continued action of the 
localized infection in the deep layers produces local circulatory dis- 
turbance, hemorrhage, anemia and so forth. Since the gastric juice 
digests devitalized tissue, and since the vascularization of the un- 
derlying tissue may become gradually less, perforation may be the 
final outcome. 

As has been stated, the rugse of the stomach mucosa disappear 
with expansion of the walls. There are two folds, however, one 
anterior and one posterior, along the esser curvature extending from 
the esophageal orifice toward the pylorus which do not disappear 
( Waldeyer) . Lewis has shown these folds on his reconstruction models 
of the stomach in the human fetus. He has described a canal along 
the lesser curvature which he named "canalis gastricus." Waldeyer 
in his review of this subject states that these folds become larger 
with the filling of the stomach and finally form a canal running length- 
wise of the lesser curvature. When a stomach is distended with air 
or fluid even to the point of rupture the lesser curvature takes compara- 
tively little part in the distention and the break always occurs at the 
fundus. I have noticed particularly that it is more difficult to get a 
good injection of the vessels in the mucosa of the lesser curvature than 
elsewhere, even with distention of the stomach. This is also true 
of the first inch of the duodenum. Mall, in his work on dogs' stomachs, 
reports similar difficulties in injecting the vessels of the pylorus and of 
the beginning of the duodenum. 

The vessels of the mucosa on the lesser curvature are not essentially 



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RELATION OF THE ARTERIES OF THE STOMACH TO ULCER 21 

different from those in the rest of the gastric mucosa. But the arteries 
making up the submucous plexus are very much smaller and make 
longer anastomoses than those in the rest of the submucosa. Due to 
the permanent folds the vessels along the lesser curvature do not have 
so great an opportunity to straighten out with moderate distention 
as those in other parts of the stomach. Thus the resistance offered . 
the blood stream by the much smaller and constantly winding tor- 
tuous arteries is never removed. As a result the blood current enter- 
ing the mucosa is constantly slower and at a lower pressure than in any 
other region of the stomach. Hence it seems the arteries are more 
liable to thrombosis. 

As I have stated, the arteries making up the submucous plexus in 
the first inch of the duodenum are comparatively few in number. 
They are rather small and do not anastomose freely. From this plexus 
we find along with others the gastric type of spiral tortuous artery 
entering the mucosa. The mucous lining is practically devoid of folds ; 
distention therefore has little effect toward the straightening out of 
these vessels. The rather limited blood supply in itself to this area 
of the duodenum probably causes a slower blood current. Further, 
the presence of gastric type of artery offers a remarkable resistance 
to the blood stream. Due to these conditions it seems that the arteries 
of the first inch of the duodenum are more liable to thrombosis than 
those of any other region. 

Conclusions 

This investigation shows that the anatomic arrangements of the 
arteries along the lesser curvature of the stomach and throughout 
the first inch of the duodenum are such that the arteries are predisposed 
to thrombosis The plexus of vessels in the submucosa on the lesser 
curvature is made up of much smaller and longer arteries without 
as free anastomoses as in other regions of the stomach. The branches 
from this plexus run a very tortuous course to enter the mucosa. The 
resistance offered the blood stream is constantly greater and, as a 
result, the blood current is slower as it enters the small arteries of 
the mucosa. The submucous plexus of arteries in the first inch of 
the duodenum is made up of relatively few vessels in comparison with 
other parts of the duodenum. They are small and do not anastomose 
freely; they give off branches to the mucosa some of which simulate 
the gastric type of spiral artery. The rather limited blood supply 



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22 T. B. REEVES 

and the gastric type of artery predispose to thrombosis. Since the 
vessels are more liable to be occluded by emboli, it is reasonable to 
suppose that they are an important factor in the production of ulcer 
by hematogenous infections. 

By these observations I wish to call attention to the character and 
distribution of the smaller arteries in stomachs and duodenums 
altogether anatomically normal, and to submit the hypothesis that 
possibly slight deviation from the normal may contribute to peptic 
ulcer. In any consideration of ulcer it must be remembered that 
this disorder is relatively and actually rare; according to Osier ulcer 
is found at 1.32 per cent of all necropsies performed in the United 
States and in Canada. Finally, it must be remembered that high grade 
bacteremias do not frequently produce gastric or duodenal ulcer. 

BIBLIOGRAPHY 

1. Bailey, F. R. : Text book of histology. New York, Wood, 5th ed., 1916, 652 pp. 

2. Baumann, A. W.: Ueber den hamorrhagischen Infarkt des Magens, hervorge- 
rufen durch embolischen Verschluss arterieller Magengefasse. Inaug.-Dissert., 
Mtinchen, 1909. 

3. Bayne-Jones, S.: The blood vessels of the heart valves. Am. Jour. Anat., 1917, 
xxi, 449-463. 

4. Cohnheim, J.: Lectures on general pathology. London, New Syndenham 
Society, 1890, iii, 878. 

5. Disse: Uber die Blutgefasse der menschlichen Magenschleimhaut, besonders 
liber die Arterien derselben. Arch. f. mikros. Anat., 1904, lxiii, 519-531. 

6. Leriche, R., and Villemin, F.: Recherches anatomiques sur Tartere coronaire 
stomachique. Bull. Soc. anat. de Paris, 1907, 6. s., ix, 224-229. 

7. Lewis, F. T. : The form of the stomach in human embryos with notes upon the 
nomenclature of the stomach. Am. Jour. Anat., 1912, xiii, 477-503. 

8. Mall, F. P.: Die Blut- und Lymphwege im Dunndarm des Hundes. Abhandl. 
d. math.-phys. CI. d. k. sach. Gesellsch. d. Wissensch., 1887-1888, xiv, 151-200. 

9. Mall, F. P.: The vessels and walls of the dog's stomach. Johns Hopkins Hosp. 
Rep., 1896, i, 1-36. 

10. Mayo, W. J. : Anemic spot on the duodenum, which may be mistaken for ulcer. 
Surg., Gynec. and Obst., 1908, vi, 600-601. 

11. Oppel, A.: Lehrbuch der vergleichenden mikroskopischen Anatomie der Wir- 
beltiere. Jena, Fischer, 1897, ii, 337-375. 

12. Osier, W.: The principles and practice of medicine. New York, Appleton, 
8th ed., 1918, p. 491. 

13. Rosenow, £. C: The causation of gastric and duodenal ulcer by streptococci. 
Jour. Inf. Dis., 1916, xix, 333-384. 

14. Virchow, R.: Historisches, Kritisches und Positives zur Lehre der Unterleibs- 
affektionen. (Paragraphs on gastric ulcer.) Arch. f. path. Anat., 1853, v, 362-364. 

15. Waldeyer: Die Magenstrasse. Sitzungsber. d. k. preuss. Akad. der Wissensch., 
1908, xxix, 595-606. 

16. Wilkie, D. P. D. : The blood supply of the duodenum. Surg., Gynec. and Obst., 
1911, xiii, 399-105. 



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ANGIOMA OF THE STOMACH* . 

W. S. LEMON 



In this report, I wish to add one more case of angioma of the 
stomach to the five of which I have knowledge, namely, the cases 
reported by Guisez, Stockis, Burty, Lammers, and, recently, one 
by Sherril and Graves. The clinical aspect of the case came under 
my observation; it was studied pathologically by Dr. Broders, who 
examined the specimen at the time of operation. 




Fig. 15 (Case A258233). — Photograph of hemangioma of the stomach as it presented 

on the mucous surface. 

Macroscopic ^examination. — The tumor was irregular in shape, 
bluish-black, rather soft, having the feel of a mass of angle worms, 
and measured 6 by 5 by 5 cm. It was surrounded by a fibrous capsule 
ranging from 1 to % mm. in thickness. Bands of fibrous tissue be- 
tween the dark angiomatous areas made it appear not unlike an 
anthracotic lung. The tumor lay between the mucosa and serosa, 

* Reprinted from Med. Rec, 1920, xcvii, 220-222. 
23 



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24 



W. S. LEMON 




Fig. 16 (Case A258233). — Photograph of hemangioma of the stomach after section. 
Note its marked lung-like appearance. 



& J2f o 




T^^fS 






^/ ^55^»jA> 




' «. i 








. 


■ 





Fig. 17 (Case A258233). — Photomicrograph of hemangioma of the stomach, showing 
a network of capillaries ( X 50) . 



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ANGIOMA OF THE STOMACH 25 

and in places it had broken through its capsule and penetrated the 
surrounding structures (Figs. 15 and 16). 

Microscopic examination. — The mass was made up of a network 
of capillaries, some showing a fairly marked dilatation. Blood 
pigment could be seen both within and without the capillaries. Some 
fields were entirely of angiomatous tissue, while others showed muscle 
with small groups of capillaries. A few clusters of lymphocytes 
were found in some of the fields. A diagnosis of capillary hemangioma 
was made (Figs. 17 and 18). 




Fig. 18 (Case A258233). — Photomicrograph of hemangioma of the stomach, showing 
patches of blood pigment in the capillaries ( X 50). 



History of the Patient 

Case A258233. Jan. 28, 1919, a man, aged 67, presented himself 
for examination, complaining of distress in the epigastric region. 
The patient was large, fully 6 feet tall, and weighed 202 pounds, 
although he showed but slight evidence of adiposity. His habits of 
life were exemplary and his trouble could not be traced to any indis- 
cretion or excess. The previous history was unimportant. Six years 
before he had had two minor operations, the correction of a varicocele, 



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26 W. S. LEMON 

and the removal of an epithelioma of the lip. After the removal of 
the epithelioma he had been treated for several months by the x-ray; 
there had been no evidence of recurrence. 

His gastric 'trouble had extended over a period of about six months; 
it had been initiated by an exhausting, but not painful, diarrhea. 
The stool was "tarry" and contained much blood. Following this 
attack and two months before his present examination, he had felt 
an indefinite aching pa n located at the left costal arch and sufficiently 
urgent and persistent to cause wakefulness and to make work almost 
impossible. The pain had taken on a diffuse character and radiated 
downward and inward toward the lower quadrants. 

Dietetic treatment had been advised, milk being used as a basis, 
but this increased rather than lessened the distress. A barium meal, 
taken when an x-ray plate was made, proved to give him great comfort. 
This meal was repeated at the end of a week. The x-ray plates of 
the stomach showed a large unfilled area in the fundus and the splenic 
flexure of the colon seemed fixed out of its normal position. The 
descending aorta was considerably dilated and was thought to have 
been so for many years, as a cough during that time had suggested 
pressure on the recurrent laryngeal nerve. 

Two weeks before examination, the patient had been conscious of 
some indefinite pain, located at the right costal margin, but his appetite 
had been good, and food taken relieved rather than distressed, 
although a certain sense of fullness with discomfort was commencing. 
He had had, however, no vomiting and no hemorrhage by mouth 
and there had never been urgent colic nor jaundice. He had lost 
25 pounds in weight, was dyspneic on exertion and easily fatigued, 
and had had a slight cyanosis. 

Physical examination revealed a loose skin, muscles somewhat 
atonic, and a loose and pendulant abdomen, adiposity 2 on a scale 
of 4, cyanosis 1, a well marked arcus senilis, and arteriosclerosis 3. 
The systolic blood pressure was from 220 to 240; the diastolic pressure 
remained constant at 120. The urine was normal with the exception 
of albumin 2, and hyaline casts 1. The pulse was 72 and regular. 
Examination of the mouth, nose, and throat revealed oral seps s and 
several carious teeth. Increased areas of dullness beneath the sternum 
and marked left ventricular hypertrophy were found, although the 
heart sounds were clear, without irregularity, and the heart itself was 
compensating satisfactorily. The lungs were clear, the liver was not 



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ANGIOMA OF THE STOMACH 



27 



enlarged, and there was no evidence of edema in the extremities. 
The epigastric area was carefully examined by several consultants; 
there was no evidence of palpable tumor or other abnormality. The 
highest readings made during the fractional examination of gastric 
contents gave a total acidity of 50 per cent and a free acidity of 30 
per cent. 




Fio. 19 (Case A258233).— X-ray of chest showing dilated aorta. 

The roentgenographs studies were interesting in that they con- 
firmed previous examinations, namely, an aneurysmal dilatation of 
the aorta (Fig. 19), the thoracic aorta taking on the appearance of a 
conical sac-like body, and a filling defect in the body of the stomach 
which the roentgenologist believed to be caused by a cancerous 
growth, the operability of which was questionable because of its 
location (Fig. 20). The one difference in the x-ray examination made 
at this clinic from that made elsewhere was the finding of what ap- 



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28 



W. 8. LEMON 



peared to be a normal colon, the displacement of the splenic flexure 
not being confirmed. 

The roentgenologist's diagnosis of cancer of the stomach was 
confirmed clinically, but in view of its location, the marked hyperten- 
sion, and the advanced age of the patient, surgical intervention was 
not advised. The patient, a surgeon himself, realizing that an explora- 




Fio. 20 (Case A258233) .—X-ray of stomach showing filling defect. 

tion promised him little, at first chose not to have an operation. 
After several days' consideration, however, he determined to take 
what little chance of improvement there m'ght be. 

At operation February 5, (W. J. Mayo) a tumor 6 by 5 by 5 cm., 
which pathologic examination proved to be an angioma, was found 
lying in the fundus of the stomach; it was quite freely movable and 
presented easily. About 11 cm. of the center of the stomach were 
removed, a sleeve resection and an end-to-end anastomosis made. 



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ANGIOMA OF THE STOMACH 29 

The convalescence was uneventful; the patient returned to his 
home on the second of March, twenty-five days after operation, 
with the wound healed. Two months later he reported that so far 
as the operation was concerned, everything had been "eminently 
satisfactory." He had a very good appetite and was able to eat 
almost everything and his early distress from sour fermenting stomach 
had improved materially. Six months after operation he was enjoying 
good health and was engaged in his medical practice. 

BIBLIOGRAPHY 

1. Burty: Un cas de volumineux, angiosarcome sous-muqueux, p6dicul£ de la grand e 
courbure de Festomac. Paris chir., 1914, vi, 731-735. 

2. Guisez: Angiome du cardia, diagnostique oesophagoscopique. Larynx, 1913, vi, 
S01-20S. 

3. Lammers, R.: Angioma ventriculi simplex. Inaug. Diss., Greilswald, Abel, 1893. 

4. Sherril, T. G., and Graves, F. S.: Hemangio-endothelio-blastoma of the stom- 
ach. Surg., Gynec. and Obst., 1915, xx, 443-446. 

5. Stockis, E.: Angiome de l'estomac chez un nouveau- ne"; mort par h£morragie. 
Ann. Soc. de m&i. leg. de Belg., 1904-1906, xvi, 61. 



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THE OPERABILITY OF CANCER OF THE STOMACH AS 
DETERMINED BY THE X-RAY* 

R. D. CARMAN 



An important diagnostic aid which can give much preoperative 
information with regard to operability of lesions of the stomach is 
the x-ray. It can demonstrate the size, the shape, and the position 
of the stomach, important factors with which the surgeon has to 
reckon, as well as the size, the location, and the extent of the lesion. 
It can show whether a stomach suspected of disease is normal, whether 
a tumor is present, and whether the tumor is intrinsic or extrinsic. 
The roentgenologist, by basing his judgment on the sum of knowledge 
gained from the x-ray, can point out whether a cancer or lesion of 
the stomach is operable or not, insofar as the stomach is concerned; 
but it remains for the internist and the surgeon to advise operation, 
and for the surgeon to decide on the kind of operation. The earlier 
the lesion is discovered, the less will be their quandary. 

Without the use of the x-ray, a diagnosis of cancer of the stomach 
is often not made until cachexia, loss of weight, achlorhydria, obstruc- 
tion, Oppler-Boas bacilli, and a palpable tumor are noted; these are 
all signs of advanced gastric cancer. The patient's fate depends too 
much on his physician's personal opinion and too little on the true 
but hidden conditions of the case. As many physicians have believed, 
and still believe, that the presence of a palpable tumor precludes 
operative relief, some patients whose lives might be prolonged by 
operation are not operated on. Others are subjected to useless explora- 
tory laparotomies which x-ray examination can prevent. 

The roentgenologist does not look on this method of examination 
as independent or ultimate, as it is only one part of a thorough clinical 
examination, and the verdict of operability based on its findings is 
only of relative value except in cases that are indisputably inoperable. 
The syndrome of early cases of cancer of the stomach is not sufficiently 

* Presented before the Section on Gastroenterology and Proctology at the Seven- 
tieth Annual Session of the American Medical Association, Atlantic City, June, 1918. 
Reprinted from Jour. Am. Med. Assn., 1919, Ixxiii, 1513-1516. 

30 



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OPERABILITY OF CANCER OF THE STOMACH 31 

characteristic to differentiate it from that of other gastric diseases, 
nor can a cellular diagnosis be made by the x-ray, but a filling defect 
may be shown which enables the roentgenologist to make a gross 
pathologic diagnosis in the majority of cases. An indication for 
operation should be recognized in the location and extent of the filling 
defect in the gastric contour, especially when we consider that 95 
per cent of all tumors of the stomach are cancerous. As metastasis 
and an extended lesion prevent operation in many more cases than 
does the location of the primary lesion, early diagnosis seems the 
surest preventive of a high gastric cancer mortality; the x-ray has 
often proved to be a means of diagnosis and of forcasting the oper- 
ability of carcinoma of the stomach at a time when clinical symptoms 
are so slight as merely to hint at malignancy. 

The eliminative value of the x-ray in gastric diagnosis applies to 
the healthy as well as to the diseased stomach. An x-ray examination 
of patients who complain of such symptoms as indigestion and dys- 
pepsia, conditions which are often manifestations of other gastric 
and extragastric disorders, may result in negative findings. The 
outline, size, shape, and position of the stomach prove that the stomach 
is normal and only the victim of reflex disturbances which the x-ray 
may aid in finding. If the x-ray examination reveals a tumor of the 
stomach, however, screen and plate findings should be studied with 
one purpose in mind — possible cure by operation. The chances for 
cure which the particular case possesses place it, according to the 
x-ray evidence of operability, in one of three groups: operable, border- 
line, or inoperable. The limits of each group are roughly marked by 
the roentgen divisions of the stomach: Group 1, tumors of the pars 
pylorica, the operable zone; Group 2, tumors of the pars media, the 
questionable or borderline zone, and Group 3, tumors of the pars 
cardiaca, the definitely inoperable zone. 

Operable Tumors 

In Group 1 are those tumors which are located in the pyloric end 
of the stomach; these are shown by the x-ray to be operable "insofar 
as the stomach is concerned." In this type are included those cases 
in which the lesion has not spread far on the stomach wall to the 
danger zone, the pars media (Fig. 21). As approximately 70 
per cent of all gastric cancers occur in the pyloric end of the stomach, 



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82 



R. D. CARMAN 



and as about 95 per cent of all lesions which encroach on the gastric 
lumen are carcinomatous, a lesion in the pyloric end should always 
make one strongly suspicious of malignancy. The character and size 
of the filling defect may also give some hint, but the question of 
malignancy which is of importance in considering the advisability 
of operation is of no importance from the standpoint of the possi- 




Fig. 21 (263349). — Filling defect and obstruction due to tumor of the pyloric 
end of the stomach. The irregularity corresponds to a palpable mass. The lesion is 
operable "so far as the stomach is concerned." 

bility of operation ; that depends on the amount of healthy stomach 
wall remaining. Often cases which present such severe symptoms 
clinically as to seem inoperable prove operable on x-ray examination, 
for even a very large palpable tumor may be resected if it is confined 
to the lower half of the stomach. While a palpable tumor does not, 
therefore, prevent surgical intervention, it does mean that the lesion 
has existed for some time and that metastasis may be present. Free 



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OPERABILITY OF CANCER OF THE STOMACH 33 

motility of the cancerous stomach favors resectability, but the signs 
which point to it may also be misleading. The filling defect may be 
atypical of cancer and the clinical symptoms alone may offer little 
explanation; but if the patient who has indefinite gastric symptoms 
has any filling defect in the contour of the stomach, whether typical 
or atypical of cancer, the chances are that a malignant growth is 
present (Fig. 22). 




Fia. 22 (134942). — A small filling defect immediately prepyloric, with obstruction. 
No corresponding palpable mass. Lesion favorable for operation. 

According to Deaver, the importance of the x-ray rests on the 
demonstration of a surgical condition in the stomach, not on the power 
of differentiating the condition. It is true that it cannot in 100 per 
cent of the cases distinguished between cancer and ulcer, and in the 
doubtful cases all other methods of differentiation must yield to ex- 
ploratory incision and pathologic examination. This exploratory 
method of diagnosis was advocated by W. J. Mayo twenty -one years 
ago. We know now, however, that the x-ray can detect the primary 
lesion in a very early stage, and if, as Deaver has stated in a recent 
article, almost half of the gastric cancers seem to have followed on ulcers, 
a lesion of the stomach cannot be too early discovered and looked on as 

'VJ-3 



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84 R. D. CARMAN 

potentially malignant. When the x-ray examination shows a tumor 
in the pyloric third, the most accessible portion of the stomach, it is 
considered operable. 

A lesion of the stomach can be pronounced operable, however, only 
with respect to the stomach, as perforation and metastasis almost 
invariably remain undiscovered until after incision. The clinician can 
prevent useless operations in some cases which are indicated as oper- 
able by the x-ray, as he can find metastasis to the rectal shelf, 




Fio. 23 (149635). — Filling defect with obstruction in the operable zone. The 
lesion was operable so far as the stomach was concerned, but proved to be inoperable 
because of metastasis found at operation. 

supraclavicular glands, umbilicus, and the skin; ascites when associated 
with a history of malignancy is a fairly reliable index of inoperability. 
Gross metastasis to the lungs and bones is roentgenological^ demon- 
strable, but it is so rare in cases of cancer of the stomach as to merit 
no more than mention in this brief discussion. Abdominal metas- 
tasis, the most frequent form, is a condition which neither the x-ray 
nor any other method of preoperative examination can discover 
and which the surgeon is unable to cope with, even when the tumor 
is in the most favorable location for resection (Fig. 23). 



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operability of cancer of the stomach 35 

Borderline Tumors 

The tumors of the second group are those which extend so 
far up on the stomach wall, into the questionable zone, that their 
resection becomes uncertain; they are classed as the border-line 
cases. These cases present the most puzzling problems of opera- 
bility from a roentgenologic standpoint. Their removal depends, as 
in the cases of Group 1, on the possibility of metastasis, plus the judg- 
ment and skill of the surgeon. The position and size of the stomach 




Fig. 24 (106837). — Gross filling defect extending into the questionable zone. 
Operability of tumors of this extent can be determined accurately only by an exploratory 
incision. The tumor was found to be inoperable because of posterior attachment. 

may be a surgical drawback; the small high-lying stomach of the 
robust person offers much greater difficulty to the operator than does 
the relaxed stomach of the asthenic person. Therefore, if the roent- 
genologist is familiar with the surgeon's technic he can better form his 
decision as to the operability of the particular case than if he knows 
nothing of the operator's dexterity and willingness to attempt resec- 
tion when the tumor lies in the borderline zone of the stomach. The 
nearer the lesion approaches the cardiac zone, the more adept must be 



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36 R. D. CARMAN 

the surgeon in order to work high up under the costal arch and to 
remove just enough of the stomach so as to leave it free from neoplasia 
(Fig. 24). 

Tumors of the fundus which do not produce pyloric nor cardiac 
obstruction, and which are not palpable because of their high location, 
may exist for some time without causing much inconvenience; by 
the time clinical diagnosis is definite, they are usually inoperable. 
Also, when a tumor is in a questionable position with regard to opera- 
bility, allowance must be made for the type of tumor and consequent 




Fig. 25 (123017). — Filling defect of greater curvature involving the operable 
and questionable zones. Operability questionable so far as the stomach is concerned. 
Operation: sleeve-resection. 

type of invasion of the stomach wall. The fungoid carcinomas pro- 
duce multiple irregular filling defects, and the real extent of the cancer 
is quite closely simulated by the roentgen shadow, while the scirrhous 
cancer produces a filling defect less gross which may gradually shade 
off and not picture the true limits of the disease. Even after al owing 
for an excess of nvolvement of a scirrhous cancer, beyond that indi- 
cated, exploration may reveal inoperable conditions (Fig. 25). As 
free mobility of a cancerous stomach favors resectability, as fixation 



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OPERABILITY OF CANCER OF THE STOMACH 37 

resulting from extension to adjacent organs makes successful inter- 
vention less probable, as cancer roentgenologically demonstrated as 
small may at operation be found to have invaded or become adherent 
to adjacent abdominal organs, and as metastasis may exist without 
detection by the x-ray, the roentgenologist is forced to make such a 
relative diagnosis of operability in the borderline group of cases that 
it might be called the exploratory group, for on the surgeon devolves 
the operative decision. 

Inoperable Tumors 

In Group 3 are the cases of gastric tumors which are pointed out 
with finality by the x-ray as inoperable. The tumors of this group are 




Fig. 26 (109449). — Tumor involving questionable and inoperable zones. A tumor in 
this location is indisputably inoperable. 

located in the cardiac end of the stomach, or they have spread from a 
pyloric or fundal carcinoma to within this inoperable zone. Surgery 
can bring no relief to the patient when the cardiac end of the stomach 
is cancerous. The tumors in this region of the stomach are easily 
recognized as inoperable by the x-ray (Figs. 26 and 27). 



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38 R. D. CARMAN 

Statistics of cancer of the stomach show an appalling number of in- 
operable cases, especially when it is considered that surgery may bring 
cure early in the course of the disease. The high fatality rate of 
cancer of the stomach may be largely attributed to too-late diagnosis. 




Fig. 27. — Tumor located in the inoperable zone. Operation is contraindicated in 

cases of this type. 

The Value of the X-ray 

Of recent methods which have so far been adapted to discover the 
cancerous growth and to prophesy the chances for its removal, the 
x-ray signs when correlated with clinical findings seem to be the most 
promising means by which operability may be increased through earlier 
diagnosis. So many seemingly benign lesions of the stomach prove 
to be malignant, that the advisability of medical treatment instead 
of operation seems very questionable or even homicidal. Periodic 
x-ray examinations in a suspected case can, of course, be made, but if 
instead of retrograde changes a filling defect typical of carcinoma is 
noted in time, attempted operation may be too late because of metas- 
tasis; the watchful waiting policy often proves not to have averted 
operation and perhaps to have been the only cause of the patient's 



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OPERABILITY OF CANCER OF THE STOMACH 39 

early death from a malignant gastric tumor. Even though a growth 
may be very extensive, if it has not invaded the cardiac end of the 
stomach the patient should be given the chance of its successful re- 
moval through exploratory laparotomy, as some cancers evidently 
metastasize later than others. The exploratory incision is of little 
danger and it may be the means of finding a growth which has not 
quite reached the dividing line between operability and inoperability, 
that is, when the dividing line represents metastasis. 

When the testimony in favor of the x-ray is collected, we find, then, 
that its only decisive value in predicting the operability of carcinoma 
of the stomach is its prevention of operation in inoperable cases. Its 
value in the borderline cases is limited to preoperative information 
with regard to the location and extent of thfe growth, and their signifi- 
cance for malignancy. In the first group, which includes the highest 
percentage of operable cases, the x-ray diagnosis of operable insofar 
as the stomach is concerned can be almost 100 per cent diagnostically 
correct while operability determined by metastatic conditions dwindles 
to about 50 per cent. As the likelihood of metastasis and the spread 
of the disease seem to increase with the age of the disease, it is an ob- 
vious corollary that many more patients could be successfully operated 
on if a diagnosis were made early. 

Until all medical men and laymen realize the necessity of early 
examinations of all persons with any gastric complaint the death rate 
from gastric cancer will remain high while the successful operability 
rate of carcinoma remains discouragingly low. Propaganda which 
will direct the public's attention to the dangers of disregarding gastric 
symptoms seems as justifiable and perhaps as necessary as the cam- 
paigns which have decreased the death rate of tuberculosis. In 1900 
the mortality statistics for all forms of tuberculosis were 201.9 for 
100,000 population; in 1916 they had dropped to 141.6, more than 60 
per cent. 3 The death rate from cancer, of which gastric cancer is the 
most common form, rose in that time from 63 to 81.8 for 100,000 popu- 
lation, more than 18 per cent. These statistics have only a relative 
value of course, but they do surely mean that the death rate from tuber- 
culosis is lower than it was eight years ago, while the death rate from 
cancer is no lower despite the advance in surgical technic. Publicity 
through national and state public health departments which will lead 
persons who are suffering from chronic indigestion or dyspepsia, which 
are not diseases but only symptoms, to consult a physician, who will 



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40 R. D. CARMAN 

conduct a thorough examination, should be one oi the means of raising 
the operability of cancer. In every such routine examination, no 
matter how slight the symptoms, an x-ray examination should be 
included. The x-ray can now discover 95 per cent of all gastric tumors, 
of which only about 50 per cent are still in the operable stage. When 
routine examinations of persons presenting gastric symptoms become 
a reality, the x-ray should be able to increase the number of operative 
cases, for the inoperable tumors should be practically only those which 
cannot be resected because of cardiac location, and carcinomas of the 
cardia represent a small per cent of gastric cancers. 

BIBLIOGRAPHY 

1. Deaver, J. B.: Early recognition of carcinoma of the stomach. New York Med. 
Jour., 1919. cix, 749-751. 

2. Mayo, W. J. : Observations upon the diagnosis and surgical treatment of certain 
diseases of the stomach, based upon personal experience. Med. Rec., 1898, liii, 836-838. 

3. Mortality statistics, 1916. Seventeenth annual report. Washington. Govern- 
ment Printing Office, 1918. 



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CANCER OF THE STOMACH AND ITS SURGICAL 

TREATMENT* 

C. H. MAYO 



Probably no word in medicine is more depressing to the patient 
than that of cancer in the diagnosis of his disease. We are assured 
by most clinicians that cancer is on the increase; possibly this increase 
is more apparent than real and is due to the greater general diagnostic 
ability of the medical profession and the better facilities for obtaining 
statistics. A general knowledge, as well as fear, of the disease is 
gradually spreading, largely the result of the propaganda of the pub- 
licity committee of the American Medical Association, and the work 
of the special cancer commissions, all of which are creating a favorable 
evolution of opinion, and causing more persons to seek treatment 
during the earlier stages of the disease. 

The most common cancer is that of the stomach. More than 
one-third of the cancers in men and more than one-fifth of the cancers 
in women appear in this organ, and inasmuch as the condition in 
nearly one-half of such patients who come to the physician for exami- 
nation is inoperable, there is room for some improvement in the matter 
of securing earlier recognition of the disease. At best, however, the 
gain will be comparatively small over present conditions, because in 
many instances the disease gives but few symptoms until it is far 
advanced, and because approximately 75 per cent of cancers of the 
stomach are so located or of such a type that early metastasis takes 
place into glands and into other organs, or the disease may become 
grafted throughout the peritoneum; to prevent this early operation is 
essential. About one-fourth of gastric cancers are confined to the 
stomach, and in this group if glands are involved they are in or con- 
nected with its wall without papillary outgrowth. These are the most 
favorable cases for operation, and yet all of this type are not operable 

* Presented before the American Surgical Association, Atlantic City, June, 1919. 
Reprinted from Ann. of Surg., 1919, bra, 237-240. 

41 



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42 C. H. MAYO 

for various reasons, advanced age, general debility, complicating 
diseases, or extensive involvement of the stomach. In the inoperable 
group may be placed the cases involving the cardia, approximating 
10 per cent of the gastric cancers. 

The literature concerning the general subject of cancer, especially 
of its etiology, is voluminous. Usually such articles are written with 
the object of proving special theories: for example, that cancer is or 
is not an hereditary disease, that it is caused by some unknown 
infection, or that this infection is water-borne, that it is due to malnutri- 
tion, general and local, and hence is a medical disease; that it is due 
to acids, especially of the sulphurous type, or to the excess of choles- 
terol. Cohnheim's theory of tissue displacement as a cause has long 
since been refuted. In taking a general survey of the various theories 
and reviewing the clinical evidence, it would seem that not one, but 
several conditions are essential to the development of cancer. The 
influence of heredity probably does not extend beyond an inherited 
cell weakness in which extra demand on the cell for division may early 
exhaust its controlling agent. The great influence of local irritation, 
which in some instances is undoubtedly chronic infection, is a fact 
quite generally accepted. No one theory, however, can account for 
the change in the cell that causes it to adopt lawless existence and to 
lose its harmony with community life. There is little change from the 
normal in the cancer cell, yet by the microscopic study of a group of 
cells and their relationship to surrounding tissues, cancer can be identi- 
fied positively. An acid condition in the surrounding fluid also seems 
essential to cancer activity. Hot drinks are probably a cause of no 
little importance in producing cancer of the stomach. 1 Chronic ulcer 
is the most important factor to be considered in these cases, as in more 
than 40 per cent there is a history of ulcer varying from many months 
to several years before the onset of cancer. When seen early such 
cancers are found to have developed on the margin of an ulcer. In 
such location the demand of cell renewal is constant; when some cell 
exhausts its controlling granules in the division, and, reverting to 
single cell type, becomes parasitic, we may have the beginning of 
cancer, but only if other factors are present. The type and growth are 
dependent on the basal cell and the environment. In a general way 
it may be said that the nucleus is proportionately larger in the cancer 
cells, and is ready for division with less than the average amount 
of cytoplasm surrounding it. Individual cells, as well as groups, must 



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SURGICAL TREATMENT OF CANCER OF THE STOMACH 43 

be studied. The various parts of the cell, taking different colors 
through the varying action of stains, show the complex chemical 
structure of the protoplasm. It is within reason to assume concerning 
the normal division of a cell that its control is the centrosome; possibly 
other granules may serve this purpose. Cell growth in cancer is 
undoubtedly stimulated by acidity or greatly lowered alkalinity. In 
this connection it is of interest to mention the work of Loeb. He 
found by a brief immersion of the unfertilized eggs of sea urchins in 
a 1 per cent solution of butyric acid and sea water, that the eggs 
became fertilized and took on active growth, without sperm. On 
the other hand, it has been shown that eggs of certain types of lower 
animals that develop in water, when placed in 0.6 per cent saline 
solution develop with frequent anomalies, especially of the higher 
nervous system, the last addition in evolutionary life. 

The greatest number of cancers come in the area of highest acidity, 
the stomach. Ninety-eight per cent of intestinal cancers are in the 
colon, while cancer in the small intestine is relatively rare — about 
2 per cent. Cancer in the urinary bladder is not uncommon, while 
in those organs with a limited period of activity, such as the breast, 
uterus, and prostate, a normal degeneration often becomes a pathologic 
one, the stimulating influence probably being of a chemical nature. 
Cancer of the duodenum is exceedingly rare, yet ulcer of the first 
portion of the duodenum is nearly four times as frequent as ulcer of 
the stomach, and while there is opportunity for involvement by 
continuity of tissue from the most frequent site of cancer in the body, 
the stomach, this does not occur. Ulcers appear in the first portion 
of the duodenum as it is bathed by the acids of the stomach before 
they are neutralized by the secretion of Brunner's glands; ulcers do 
not appear in the alkaline portion of the intestine below the common 
duct, although they may be found in a gastrojejunal opening which 
has there been rendered acid. 

While I am not presenting this subject from the standpoint of 
diagnosis, I wish to refer to the progress which has been made in the 
diagnosis of gastric cancer, and to corroborate Carman's observations 
on the operability of cancer of the stomach as determined by the x-ray. 
Without the x-ray we would be back to the old methods of determining 
diagnosis, namely, by cachexia, loss of weight, achlorhydria, obstruc- 
tion, tumors, and so forth, which are all signs of advanced gastric cancer. 
At a time when the cancer syndrome is not positive but probable, the 



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44 C. H. MAYO 

x-ray may be relied on to demonstrate lesions of the stomach in more 
than 95 per cent of the cases. 

In general the treatment of cancer by radium is proving successful 
in certain types of the disease which can be reached by the ray; in 
some instances cure is produced and in others growth is delayed. By 
care and filtering processes the various rays are controlled. The effect 
on the cell is chemical, influencing the protoplasm or the local fluids. 
Radium is most effective in growths with active circulation, as it has a 
marked influence on the wall of the blood vessel. It also apparently 
acts on the cell nucleus, checking division, but it may be used to excess 
and cause local destruction. The x-ray acts on the cell protoplasm, 
checking growth, and it may also cause local destruction. Between 
these two conditions, the x-ray causes rapid epithelial proliferation, 
areas of which might at times be called precancerous. The cell, 
having lost its controlling granules through the ray's action and re- 
taining its nucleus and cytoplasm, will become malignant when sur- 
rounded by the proper biochemic fluids. This shows that under 
certain conditions cancer can not only be produced but controlled. 
As yet radium and x-ray are only palliative or a means of delaying 
the progress of gastric cancer. 

From Oct. 1, 1897, to Jan. 1, 1919, we performed 2094 opera- 
tions for cancer of the stomach. Seven hundred and thirty-six of 
these were resections with a mortality of 13.7 per cent, 746 were 
explorations with a mortality of 2.9 per cent, and 612 were palliative 
operations with a mortality of 11.1 per cent. The common type of 
operation was the Mikulicz, Hartmann, Billroth No. 2, of which there 
were 359, with a mortality of 12.5 per cent. There were 19 of the 
Billroth No. 1 type with a 5 per cent mortality, 28 sleeve resections 
and 7 Kocher operations with a mortality of 14.2 per cent each, 115 
posterior Polya operations with a mortality of 14.7 per cent, and 
120 anterior Polyas with a mortality of 13.3 per cent. The local 
resections, 12 in number, gave the highest mortality, 25 per cent. 
These 660 resections have been done since 1906. Prior to this the 
type of resection was not described in the records definitely enough to 
be included in a statistical report. The Billroth No. 1 operation con- 
sists of a resection of the pyloric end of the stomach, and the suturing 
of the duodenum to the partially closed distal end of the remaining 
portion of the stomach. Since the Y-shaped line of suture of this type 
of operation frequently leaked, with fatal results, Billroth, with Mik- 



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SURGICAL TREATMENT OF CANCER OF THE STOMACH 



45 



ulicz and Hartmann, developed the so-called Billroth No. 2 operation, 
which consisted of completely closing the end of the stomach and mak- 
ing a posterior gastrojejunostomy. The Kocher operation avoids the 



Invertxa 
suture oj 
catgut 




Duodenum 



Purse -^tctn^ 
su/ture tuedL^ 



late ruu.pt ed, 
Sbik 
5 at are s 




%nd purse -struxg 
sat are oj catgut ^g ' wgr- 

or silk ^'^ 6 astro - 

\&p<^ coLlc oTTteruttcrrb 
Fig. 23. — Two methods of closing and protecting the cut end of the duodenum. 

leakage of the Billroth No. 1 operation by attaching the end of the 
duodenum through an opening in the posterior wall of the stomach 
after the open end is closed, but tension here occasionally gave obstruct- 
ive trouble or leakage (Figs. 28 and 29). Polya avoided the double 



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46 



C. H. MAYO 



operation of closure of the end of the stomach followed by gastro- 
enterostomy by uniting, retrocolic, the entire open end of the stomach 
to an equal sized opening made in the jejunum. In the Polya opera- 
tion the newly formed end of the stomach consists of the jejunum, 
which spreads out as the stomach is filled; the opening may be from 
3 to 5 inches in length, according to the size of the resected end of 



Interlock/und stutoK 



Stomack 




J- u-fautrt--. 



Fig. 29. — Jejunal attachment; approximate size of opening in bowel. 

the stomach. If the opening is but 3 inches, the whole end of the 
stomach may be attached to the jejunum by incising the bowel a nearly 
equal distance; with each passing of the needle, the suturing loops 
catch a somewhat greater amount of the wall of the stomach than of 
the bowel. Since the bowel becomes the stretched-out end of the 
stomach with an opening at each side of the attachment, proximal 
and distal, the delivery of gastric contents is not so well accomplished 



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SURGICAL TREATMENT OF CANCER OF THE STOMACH 



47 



as it is with the partially closed end of the stomach with an ordinary 
sized gastroenterostomy opening properly placed (Fig. 30). The 




Fio. 30. — Gastroenterostomy opening with partially closed end of the stomach. 

mortality rate incident to the various operative methods is nearly the 
same; there is, however, some difference in the comfort and post- 
operative condition of the patient. In the operation described here- 



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48 



C. H. MAYO 



with this large opening is avoided by attaching the jejunum to the 
posterior wall of the stomach close to the crushing clamps, which are 
left on to hold the stomach closed until the first row of sutures is 
applied. Before removing the crushing forceps the contents of the 
stomach are controlled by applying long, flexible rubber-covered 
forceps, slightly higher on the stomach, which prevent its contents 



R.e"bu/tTVirid 



StoTTLacK 




Jeju/rvLurrb 



Fig. 31. — Catgut suture closing gastrojejunal opening and continuing over the closed 
portion of the stomach to reinforce the suture line. 

from soiling the wound. After the first row of sutures has been made 
and the crushing forceps removed, the stomach is partially closed 
by an inturning suture, begun at the greater curvature, closing in 
toward the lesser curvature until the opening remaining is only slightly 
greater than the diameter of the jejunum. The jejunum is now opened 
opposite this point, a quarter of an inch from the first suture line, and 



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SURGICAL TREATMENT OF CANCER OF THE STOMACH 



49 



the ordinary technic of gastro-enterostomy is completed. The opening 
being closed, the suture is continued as a second row over the closed 
portion of the end of the stomach. The first suture is now continued 
over the anterior portion, making two rows on the gastro-enterostomy 



Di>staJL TenixruLLTrL 



StoTrtaLo}t 



etu-rrum^ 




swbure 
-je-jLLnuurrL 

Fig. 32. — Final row, serous "suture completing suture line which protects the end of 
the stomach with the intestine. 

opening, and protecting still further the closed end of the stomach 
by suturing over it the unopened bowel (Fig. 31). 

For the last three years we have been doing the anterior Polya, the 

'19-4 



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50 



C. H. MAYO 



original Kroenlein instead of the posterior, bringing the loop of jejunum 
over the transverse colon. We abandoned the posterior Polya because 
of primary obstructive complications due to adhesions, to tension from 
gastric traction, or to late trouble from recurrence of the malignancy, 
with early obstruction. The anterior operation gives an easier conva- 
lescence on the average (Fig. 32). I believe that better after-results 
are secured by turning the bowel to the right, isoperistaltic, which was 



EsopKatfuts 



Splervbc 
ex are 




Fig. 33. — Schematic diagram. 



Method of attaching jejunum and stomach, 
turn not shown. 



Omen- 



a marked feature in the earlier operations of anterior gastroente- 
rostomy. The point of attachment of the jejunum is approximately 
fourteen inches from its origin, while the opening in the stomach comes 
directly over the descending leg of its loop, the reverse of the Mikulicz 
partial closure and button anastomosis. The transverse colon natu- 
rally sags in its mid portion; by turning the bowel from left to right it is 
brought to the left of the center, while the stomach delivers along its 
lesser curvature the more fixed portion of the viscus. Inasmuch 
as the tissues of the stomach are more or less devitalized by disease 



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SURGICAL TREATMENT OF CANCER OF THE STOMACH 51 

and more so by the operation, the suture material recommended is 
silk for the outer row and chromic catgut for the inner row; the silk 
guards against separation from delayed healing (Fig. 33). The com- 
pleted operation can be made within one hour. 

Our data bring the results of operation up to Sept. 1, 1917. Four 
hundred and twenty-seven patients were operated on during the 
three years previous to September, 1917. Those who died in the hos- 
pital and those not heard from number 121. Those who recovered 
from the operation and who have been heard from number 306; 115 
(37.6 per cent) of these show three-year cures. Three hundred thirteen 
patients were operated on during more than five years before Sept. 
1, 1917. Those who died in the hospital and those not heard from 
number 79. Those who recovered from the operation and who have 
been heard from number 234; 59 (25 per cent) of these show five- 
year cures. This is a most satisfactory showing for the surgical 
relief of an otherwise hopeless condition which is attended by much 

suffering. 

BIBLIOGRAPHY 

1. Mayo, W. J.: Cancer of the stomach. Surg., Gynec. and Obst., 1918, xxvi, 
867-370. 



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DIAGNOSIS OF LATE RECURRENCES FOLLOWING 
GASTRO-ENTEROSTOMY: A PRELIMINARY RE- 
PORT ON 84 CASES OF GASTROJEJUNAL 

ULCER* 

G. B. EUSTERMAN 

This subject is of particular interest because the determination of 
factors underlying late sequelae is, under certain circumstances, the 
most difficult of gastro-enterologic diagnosis. Representative of 
these disappointments after surgery is gastrojejunal ulcer, a consider- 
able number of which have gradually come under our observation, 
and which I have reviewed in the latter part of this paper. The 
subject matter incidentally affords the internist an opportunity to 
express certain convictions on an important phase of surgical therapy, 
both with regard to its virtues and its shortcomings. 

That the ultimate results of the surgical treatment of ulcer-bearing 
patients is not uniformly successful is generally known, and conceded 
by the surgeon, 78 - 911 yet everything considered, there is no cause 
for serious apprehension on the part of our surgical conferres, notwith- 
standing the tenor of certain current contributions on the subject 
or the disheartening percentages of surgical failures advanced in 
discussion. Much of the criticism of surgical end results seems to 
have been inspired and therefore unfair, while in other instances it 
was constructive in that the medical man, while admitting his own 
as well as the surgeon's share in the therapeutic failure, proposed 
remedial measures to circumvent the latter. It has been my experience 
that fair criticism is always welcomed by the rank and file of the surgical 
profession who are always open to conviction, invariably ready to 
adopt any procedure the efficacy of which has been proved to them. 
It is not within the province of this paper to discuss the relative merits 
of purely intensive medical or surgical treatment; the ulcer problem, 
however, is generally medical both before and after operation, but under 
certain conditions it is always surgical. There is a definite middle 
ground on which the internist and the surgeon can always meet, to 

* Presented before the Southern Minnesota Medical Association, Mankato, 

December, 1919. 
52 



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GASTROENTEROSTOMY 53 

say nothing of the many instances in which they might pool their 
therapeutic resources. The extreme views as to treatment too freely 
expressed by representatives of both factions only serves to delay 
that rapprochement so necessary to the best interest of the patient. 

My observations have convinced me that the so-called medical 
treatment of ulcer has been incomplete, haphazard, and largely aiming 
at symptomatic relief in 90 per cent of the patients. Naturally a 
permanent cure is rarely achieved. In the minds of many medical 
men, including surgeons, such results unjustly condemn the method, 
both in practice and principle. As a consequence many patients be- 
come decided* 'chronics;" they often suffer from severe relapses and 
complications, and eventually seek relief in surgery. A gratifying 
majority are permanently cured or markedly improved thereby, without 
any recourse to other measures or restrictions. 6 There remains a con- 
siderable number, classified as improved and unimproved, including 
those with late serious sequelae, which could be reduced appreciably 
by proper medical management. I believe that the surgeon in the 
past has too often stood in the way of his own success. 

Good results in the treatment of many chronic ambulatory diseases 
often depend on the cooperation of the patient and his ability, through 
proper training by the physician, to treat himself. Familiar examples 
are the diabetic and tuberculous patient, the salutary effect of whose 
management and intimate instructions in hospital or sanatorium 
cannot be gainsaid. In the past few years marked immediate and 
remote beneficial effects have been recorded in several hundred gastro- 
enterostomized patients who have been instructed in those essential 
details regarding the nature and preparation of their food, habits, 
symptoms, proper use of alkalies, and other equally important measures. 

Immediate and remote factors frequently unfavorable to ultimate 
surgical success are always present. Flint and others have shown 
that the anastomotic area is the site of a healing ulcerated surface 
for a period of fourteen days and that this healing is not always com- 
plete at the end of that time. It is now generally conceded that 
ulcers of the stomach and duodenum are largely embolic infections 
from some distant focus of infection. In other words, the presence 
of an ulcer should be considered good evidence for the existence of a 
remote focus of infection. 12 Finally, hyperacidity and hypersecre- 
tion, pylorospasm, and disturbed motility are known to make their 
reappearance by virtue of temperament, dyscrasia, vagotony, or 



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54 G. B. EUSTERMAN 

indiscretion, and to work mischief sooner or later. Such a situation 
has a peculiar appeal to the internist rather than to the surgeon, and 
it is succesf ully met by a carefully supervised immediate postoperative 
diet, devoid of premature, bulky, traumatizing elements, by the 
intelligent routine removal of provocative foci in teeth or tonsils, and 
finally by a later graduated system of diet, alkali therapy whenever 
indicated', and attention to other individual details. These are 
measures which prevent distressing functional disorders and subse- 
quent formidable sequelae. Skepticism on the part of the profession 
regarding the capacity for healing and the correction of vices of secre- 
tion through painstaking medical management, which includes the 
removal of foci of infection whenever indicated, is based on ignorance 
and prejudice rather than on fact. 

Certain trends in present day gastric surgery give reassurance that 
many of the shortcomings and errors of the past which have on oc- 
casions reflected discredit will not obtain in the future. Chief among 
these are the disinclination to operate first and to diagnose afterward; 
to eradicate the ulcer-bearing area whenever possible; to refuse to 
operate on the stomach in the absence of a "visible, demonstrable 
and palpable lesion," 11 and to explore routinely and remove any 
diseased organs of the accessory digestive tract. Under the latter 
circumstance surgical procedure has an inherent advantage in some 
cases in which gallbladder and appendiceal disease frequently co-exist 
with ulcer, and in which operation is primarily performed for a sup- 
posed ulcer, and the cause of the painful indigestion is found to be 
reflexly engendered by gross disease in one or both of the other organs. 
Obviously no form of medical treatment could permanently relieve 
the latter situation. • 

The immediate complications following gastrojejunostomy, such 
as hemorrhage, vicious circle, acute dilatation, and so forth, will not be 
discussed here. A perfected technic makes such features increasingly 
rare, but I shall very shortly consider more fully those causes giving 
rise to late, painful recurrences, identical with, or similar to, the pre- 
operative symptoms. However, the various reasons for disappoint- 
ment or failure after gastroenterostomy should be stated since they 
must be considered in arriving at a diagnosis, especially if the operation 
was performed elsewhere. Such causes may be classified as follows: 

1. Operation performed in the absence of a lesion intrinsic to the 
stomach or duodenum. — In this group would be included the functional 



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GASTROENTEROSTOMY 55 

gastric disorders which occur in neurotic and asthenic persons, ill- 
defined disturbances of the autonomic nervous system, including 
nervous vomiting, pylorospasm, instances of visceroptosis, achylias 
simulating the ulcer syndrome, atonic and dilated stomach, gall- 
bladder disease, appendiceal dyspepsia, gastric crises of tabes, splenic 
anemia of various grades, often associated with hematemesis and 
melena, hepatic cirrhosis, hyperplastic tuberculosis of the intestines, 
epigastric hernia, prolapse of the right kidney, and colonic adhesions 
and membranes. 

The so-called functional cases, those in which no evidence of a 
pre-existing ulcer was found and in the majority of which no other 
intra-abdominal disease was noted easily constitute more than two- 
thirds of the surgical failures. This is evidenced by the fact that 
my surgical colleagues have undone more than 300 gastroenterosto- 
mies performed elsewhere, as well as some of their own of an early 
period. I might add, that some neurotic persons with actual lesions 
either of the stomach or of the accessory digestive organs fail to improve 
after skillful surgical interference because their trouble was primarily 
of neurotic origin; also that an atonic, flabby ulcer-bearing stomach, 
usually found in an asthenic person, continues to give trouble after 
operation. 

2. Errors or defects in technic. — Chief among these are: a stoma 
that was made too large or too small, or improperly placed; a long 
jejunal loop; improper application of jejunum to stomach so that the 
direction of the proximal short portion of the jejunum is from left 
to right; a kink or angulation in the efferent limb of the jejunum, or 
obstruction to the proximal loop; hernia of the small intestines into 
the lesser cavity; and the use of unabsorbable sutures. Some of these 
fortunately rare surgical shortcomings are sooner or later followed by 
symptoms alarming enough to make a secondary operation imperative. 

3. Lack of thoroughness in operating. — An example of the lack of 
thoroughness in operating is the failure to remove a diseased gall- 
bladder or appendix at the time of an otherwise successful operation. 
If the patient's condition warrants it some authorities believe that 
it is expedient to remove the appendix in all abdominal operations. 
Failure to deal directly with the ulcer by cautery or knife excision, 
or at least by enfolding, will not insure against reactivity in the ulcer 
and the result will be a recurrence of original symptoms, especially 
hemorrhage. 1 ' * 



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56 G. B. EUSTERMAN 

4. Late complications. — To the group of late complications l>elong 
the cases in which the recurring trouble is chiefly of a painful nature* 
usually identical with or similar to the original symptoms for which 
the patient sought relief. The onset of such symptoms may follow 
soon on the operation, or they may not appear for a number of years, 
or the original symptoms, somewhat abated, may have continued 
since operation. The four main underlying causes are gastrojejunal 
ulcer, reactivity in the original partially healed or unhealed ulcer, 
carcinomatous changes in a chronic gastric ulcer, or the formation 
of a new ulcer in the duodenum or stomach. To a lesser degree, 
adhesions in the region of the pylorus from natural causes, or as the 
result of too much manipulation or repeated operations, cripple 
gastric function and provoke distressing symptoms. It is in such 
types that the greatest difficulty is encountered in determining the 
factor or factors underlying the complaint. This is especially true 
in the early stages of the trouble when thorough medical or surgical 
treatment promises the most, and when combined clinical and labora- 
tory diagnostic procedure is not sufficiently informative. Successful 
differential diagnosis presupposes a thorough knowledge whenever 
possible of symptoms and conditions existing before operation, during 
operation, and after operation, especially with reference to whether 
or not an ulcer actually existed, gastroenterostomy was done, or 
some procedure was carried out on the ulcer or pylorus. Any difficul- 
ties encountered during the operation, or immediate postoperative 
sequelae, have especial significance. In the absence of reliable infor- 
mation the physician is thrown on his own diagnostic resources. In 
the examination special attention is paid to hyperacidity and hyper- 
secretion, gastric motility, nine and twelve hours after a Riegel meal, 
blood in gastric extract and feces, palpable masses, and visible 
peristalsis. The barium motor meal and fluoroscopic examination 
are particularly valuable in visualizing new ulcers; this procedure 
occasionally gives reliable information with respect to the status of 
the original ulcer, of gastric motility, and of the roentgen ray charac- 
teristics of ulceration at the stoma. 4 

From a study of the postoperative condition of our patients in 
whom a definite ulcer was found and a uniform type of posterior no- 
loop gastrojejunostomy was done, with removal of any coexisting 
abdominal disease, I have drawn some general conclusions. As soon 
as the immediate effects of the operation have passed, the patient 



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GA8TRO-ENTEROSTOMY 57 

experiences relief from the pain and associated symptoms suffered 
for a certain period after taking food, and an increase in weight and 
strength. This state of normal gastric function may continue there- 
after without any special dietetic precautions. In a second group 
the patients may have periods of mild or moderately severe gastric 
disturbances from six to twelve months after operation; then without 
any definite measures for relief the symptoms subside permanently. 
Patients of a third group in whom a gastroenterostomy is done for 
uncomplicated duodenal ulcer associated with hyperacidity, hyperse- 
cretion, and active peristalsis have a recurrence of the original trouble, 
and routine re-examination fails to reveal any organic cause. The 
inference follows that the old ulcer has become reactivated. Proper 
diet and alkali therapy, the removal of foci of infection, and the cor- 
rection of bad habits cause marked amelioration or permanent relief 
of all symptoms. Pyloric occlusion, exclusion, or enfolding of the 
ulcer has not been successful. The slow progressive pyloric obstruc- 
tion by a cicatrizing ulcer or inflammatory edema, or both, in an 
organ ripe for a gastroenterostomy is a different proposition from a 
sudden artificial occlusion. Here should rightly be included and due 
allowance made for a considerable number who fail to get the relief 
they should from operation, and who belong to what might, briefly 
stated, be called the neurotic group. Many of their symptoms pre- 
vious to the operation were of a character not easily explained by 
ulcer; their symptoms continue and are aggravated by an unstable 
nervous system reacting to the disappointment of not being cured. 
A smaller but interesting group of patients with similar clinical 
features present themselves after several years, at least, of complete 
comfort, and on examination or secondary operation are found to 
have a new ulcer in either duodenum or stomach (not a common 
occurrence), or a carcinomatous change in the primary gastric ulcer. 
We have record of 29 instances of the latter. 

Gastrojejunal (pseudo-jejunal, jejunal) ulcer alone remains to be 
considered. It is to be remembered at all times that this formidable 
complication may be the cause of recurring symptoms early or late 
in the postsurgical period. In symptomatology it may differ little 
from the other causes mentioned, but its invariably progressive course, 
yielding slowly, incompletely, and frequently only temporarily, to 
careful medical management should arouse suspicion of its pres- 
ence. Before considering this lesion more fully, some observations 



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58 6. B. EUSTERMAN 

regarding the postsurgical disturbances following pyloroplasty are 
pertinent. 

The end-results following pyloroplasty in our cases have not been 
so satisfactory as the results following gastrojejunostomy, in spite 
of the favorable circumstances under which the operation usually 
was performed- The patients having a recurrence of trouble often 
complained as before, and frequently without demonstrable secretory 
or motor disturbance. In others gross retention was present beside 
pain and sensitiveness in the field of operation. Spasm, adhesions, 
and recurring ulceration in the operative field, single or in combination, 
are causes to explain the failure to restore health. Under any circum- 
stance a secondary gastroenterostomy gives prompt, permanent relief. 

Gastrojejunal ulcer. — The two series studied are comprised of 84 cases, 
48 of which followed gastro-enterostomy performed in the clinic for 
a benign gastric or duodenal lesion, and 36 followed gastro-enterostomy 
done elsewhere. Interesting observations on a large series of such 
cases have been made by von Key, Paterson, von Roengen, Lieblein, 
Moynihan, and others. W. J. Mayo and C. H. Mayo have contrib- 
uted from time to time directly or indirectly to the subject, and more 
recently other contributions have been made from the clinic by 
Carman and Balfour, and Butsch, and others. I am reviewing the 
subject at this time primarily because of the considerable number 
of cases under observation and to call attention to the features that 
were prominent in the recognition of the lesion. To the present time 
about 3700 gastroenterostomies have been performed in the Mayo 
Clinic for benign disease. During this time 48 gastrojejunal ulcers 
have come to operation. This probably does not represent all the 
gastrojejunal ulcers that have occurred because some have been 
operated on or treated elsewhere, and others are still giving trouble. 
It is also possible that some of these ulcers healed spontaneously after 
giving more or less trouble. Therefore, at least 1.3 per cent of all 
gastroenterostomies are resubmitted to operation for ulceration at 
the stoma. In 98 per cent of these a posterior gastroenterostomy had 
been done. 

The second point of some significance is the fact that the ratio of the 
males to females in our entire series, including the series in which 
primary operation was performed elsewhere, was about 7 to 1; in 
primary benign gastric and duodenal ulcer the average ratio is about 
3 to 1, so that many more males than females suffer from this condition 



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GASTROENTEROSTOMY 59 

In a review of the clinical histories, some of which lacked essential 
details, four types of cases were recorded: (1) Cases with postoperative 
complaint almost identical with the preoperative, history, (2); cases 
with a history of irregular ulcer, (3) cases of purely intestinal type 
with symptoms largely of pain and other disturbances referred 
to the lower abdomen, associated with bloating, occasional diarrhea, 
or severe constipation alternating with diarrhea, at times present- 
ing a picture identical with that of intestinal obstruction; and 
(4) infrequent cases characterized chiefly by obstruction, perfora- 
tion, or by a sudden onset of hemorrhage with or without a brief 
history of antecedent pain, not unlike conditions obtaining in a primary 
ulcer. The hemorrhage may or may not be repeated and is often 
first induced by unusual exertion or jarring. In a majority of our own 
cases the purely gastric ulcer type of syndrome sooner or later made 
itself evident, that is, the onset of pain after meals was earlier, and 
relief by the usual measures less distinct or brief in its effect. Relief 
by soda was more noticeable; nausea, vomiting, flatulency, nocturnal 
pain, loss of weight, and a more frequent repetition of the attacks were 
some of the predominant clinical features. 

If gastrojejunal ulcer is suspected an idea of the pathologic process 
is often helpful in eliciting a more detailed history. This type of ulcer 
usually does not have a crater; morphologically it is more like the 
saddle ulcer of the stomach. It usually involves the distal segment 
of the anastomosis opposite the stoma and spreads .superficially, 
especially over the gastric area neighboring the ulceration; the base, 
of the ulcer is usually in the transverse mesocolon, involving the colon 
itself or rarely penetrating the colon, in the latter case forming a 
gastrocolonic fistula; or the ulcer may point outwardly with its base 
in the abdominal wall where the mass or the inflammatory thickening, 
or abscess, is apparent. Such a mass is more readily palpable if the 
anterior gastroenterostomy is performed. Subacute or chronic 
perforation is a frequent complication. At times it is the cause of con- 
siderable pain or local soreness, tenderness or tumefaction. Pain on 
turning or twisting of the body, raising of arms, or during a lifting strain 
is usually evidence of adhesions involving the abdominal parietes. By 
virtue of the location of the gastrojejunal ulcer, the subjective pain and 
objective mass of tenderness are frequently lower than before operation. 

In our series of 48 patients, 19 (40 per cent) definitely stated that 
their pain and soreness or tenderness were situated lower, in the 



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60 G. B. EUSTERMAN 

region of the umbilicus, than prior to operation. In 7 of these the 
postoperative symptoms were entirely left-sided. The incidence of 
hemorrhage was about the same as in the ordinary ulcer, 25 per cent. 
The presence of a tumor, mobile and usually non-sensitive, situated 
in the region of the navel, is of the greatest diagnostic importance, 
other things being equal. 

Another feature influencing the symptomatology is the reactivation 
of the old ulcer, probably the result of disturbed motility and hyper- 
acidity, or the occasional formation of a new ulcer. In our series this 
reactivation was noticed in 6 instances and a new ulcer was found 
in 2. In the 36 cases in which the primary operation was done 
elsewhere reactivation was distinctly noticed by the surgeons in 7, 
and probably in 9, or 25 per cent. The gastric analysis showed vari- 
able degrees of acidity; the average acid values showed a high normal 
acidity both for total acids and free hydrochloric. Hypersecretion 
was the rule and gross food or barium retention was present in about 
25 per cent. Occult blood in the gastric extract was present in about 
25 per cent. The time of onset of symptoms after operation was of 
interest. In our series 35 per cent had a recurrence of symptoms 
within six months; 56 per cent within a year; and, including the 
patients who experienced only partial or no relief, 88 per cent were 
complaining within one year after the original operation. In the 
group operated on elsewhere the percentage was about the same; 
in 12 cases (33J£ per cent) there was no evidence of primary ulcer at 
the time of the second operation. This, among other factors, points 
to the inference that the cause of gas tro jejunal ulcer is largely some 
defect in the operation itself. In 14 of the patients nonabsorbable 
silk or linen stitches were found hanging loose in the anastomotic area, 
and in 7 cases of our series linen thread seemed to be definitely re- 
sponsible for the trouble. That this is not the sole cause is evidenced 
by the fact that gastrojejunal ulcer has been found on several occasions 
since the use of absorbable sutures, although the incidence promises 
to be considerably less on account of this method. 

The x-ray findings are of primary importance and often render a 
diagnosis conclusive. Carman calls attention to various x-ray phe- 
nomena in the presence of a gastrojejunal ulcer, for example, deformity 
of contour about the stoma, exaggerated peristalsis, gastroenteros- 
tomy not freely patent, barium retention, spasticity of the stomach, 
and so forth. In our series of 48 cases of which 40 underwent x-ray 



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G ASTKO-ENTEROSTOM Y 6 1 

examination an unequivocal diagnosis of gastro jejunal ulcer was made 
in 18 cases; incomplete but contributory evidence was found in 14 
others. Therefore in a total of 80 per cent of the cases helpful or con- 
clusive information was obtained from the x-ray. In 8 (20 per cent) 
the findings were negative. In 36 cases in which the primary opera- 
tion was done elsewhere and in all of which fluoroscopy was done, the 
positive and contributory diagnosis was made in more than 55 per 
cent. A clinical diagnosis of gastro jejunal ulcer was made primarily 
or secondarily on an average of 75 per cent in both series of cases. The 
operative mortality was about 2.5 per cent. The patients cured and 
much improved in the 48 cases averaged about 35 per cent. In the 
36 cases the cured or much improved were 25 per cent. One reason 
for this lower percentage of cures is that the patient is merely restored 
to his pre-operative condition after the gastroenterostomy is cut off, 
or a pyloroplasty is done under unfavorable cond ; tions. The immediate 
operative mortality was 5.5 per cent. 

Conclusions 

1. Gastrojejunal ulcer is a serious complication following gastro- 
enterostomy and occurs in from 1.5 per cent to 2 per cent of cases; 
1.3 per cent of our patients have been submitted to a secondary 
operation. 

2. The ratio of males to females is 7 to 1, which is two and one-half 
times greater than the ratio in primary benign ulcer. 

3. The symptomatology closely approaches that of benign ulcer. 
The course is usually rapidly progressive, and in the majority of cases 
tends to assume that of the purely gastric ulcer type; or the symptoms 
may be purely of intestinal origin, of pyloric obstruction, perforation, 
or hemorrhage. Fistulous connection with the colon is infrequent. 
The lesion is refractory to medical treatment. 

4. A palpable mass was present in 10 of 84 cases (12 per cent). 
This is of great diagnostic importance. Hemorrhage occurs in about 
25 per cent. Pre-existing ulcers tend to reactivation, or occasionally 
a new ulcer forms. Marked twelve-hour retention of food indicates 
narrowing of the stoma, and pyloric obstruction because of strictures 
from healed ulcer or previous artificial closure. 

5. The x-ray furnished reliable direct or corroborative evidence in 
65 per cent of the cases. X-ray data in the later series are conclusive 



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62 6. B. EUSTERMAN 

in a high percentage, denoting progressive accuracy by virtue of 
accumulative experience. 

6. Gastrojejunal ulcer is caused chiefly by a mishap in the operative 
technic. In 35 per cent in which there was no evidence of ulcer prior 
to gastroenterostomy, gastrojejunal ulcer had formed. Secondary 
causes are the use of nonabsorbable sutures, severe focal infection, and 
trauma soon after operation associated with hyperchlorhydria and 
stasis. 

7. Cure or improvement following secondary operation is obtained 
in about 35 per cent of the cases. 

8. Careful operative technic combined with immediate and con- 
tinued postoperative intensive medical management should greatly 
reduce the incidence of this formidable complication. Medical 
participation under any circumstance in addition to the removal of 
foci of infection insures satisfactory surgical end-results. 

BIBLIOGRAPHY 

1. Balfour, D. C: The surgical significance of gastric hemorrhage. Jour. Am. Med. 
Assn., 1917, lxix, 465-466. 

2. Balfour, D. C. : Cautery excision of gastric ulcer. Ann. Surg., 1918, Ixvii, 725- 
731. 

3. Butsch, J. L. : Ulcers of the gastro-intestinal tract with special reference to gas- 
trojejunal ulcers. (Unpublished thesis.). 

4. Carman, R. D., and Balfour, D. C: Gastrojejunal ulcers: Their roentgenologic 
and surgical aspects. Jour. Am. Med. Assn., 1915, lxv, 227-232. 

5. Flint, J. M.: The healing of gastro-intestinal anastomosis. Ann. Surg., 1917, 
lxv, 202-221. 

6. Graham, C: Observations on peptic ulcers. Boston Med. and Surg. Jour., 1914, 
clxx, 221-226. 

7. Hutchins, R.: Disappointments after gastroenterostomy. Brit. Med. Jour., 
1919, I, 535-536. 

8. Mayo, C. H.: Causes of failures in gastroenterostomies. St. Paul Med. Jour., 
1915, xvii, 90-99. 

9. Mayo, W. J. : Recurrences of ulcer of the duodenum following operation. Boston 
Med. and Surg. Jour., 1914, clxx, 149-151. 

10. Mayo, W. J.: Gastrojejunal ulcer (pseudo jejunal ulcers). Surg., Gynec. and 
Obst., 1910, x, 227-229. 

11. Moynihan, B.: Disappointments after gastroenterostomy. Brit. Med. Jour., 
1919, II, 3S-36. 

12. Rosenow, E. C: Pathogenesis of spontaneous and experimental appendicitis, 
ulcer of the stomach and cholecystitis. Jour. Ind. State Med. Assn., 1915, viii, 458-461. 



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AN EXPERIMENTAL STUDY OF THE EFFECTS OF 
DUODENECTOMY 

A Preliminary Report* 

f. c. MANN 

AND 

K. KAWAMURA 



The scope of this investigation of the effect of duodenectomy in 
dogs is twofold: (1) to determine whether the duodenum is absolutely 
necessary to life, and (2) to determine its rdle in the functioning of 
the gastro-intestinal canal. 

From a practical surgical standpoint, duodenectomy is probably 
of very little consequence, although several partial resections have 
been performed satisfactorily. From the physiologic point of view, 
however, the operation is significant. The duodenum occupies a very 
important anatomic and physiologic position just distal to the stomach, 
and is seemingly intimately associated with the physiology of that 
organ, with special reference to its mechanism for emptying. The 
liver and pancreas discharge their secretions into the duodenum, 
which bears some relation to the manner in which these organs function- 
ate. In addition to this, the duodenum itself elaborates a secretion 
and contains glands (Brunner's) which are found only in this part of 
the body. It is thus possible that the duodenum is of importance 
in the general physiology of the organism and plays a necessary part 
in the function of the gastro-intestinal tract and in digestion. It 
seems logical, therefore, to believe that the removal of the duodenum 
will produce noticeable effects, and that the compensation of the body 
to its removal will make possible an evaluation of its real importance. 
The first experiments recorded in the literature of the removal of 
the duodenum were made for the primary purpose of attempting to 
determine the relative part the duodenum and pancreas play in the 
production of experimental diabetes, and not for the purpose of 

• Read before the Section on Pathology and Physiology at the Seventieth Annual 
Session of the American Medical Association, Atlantic City, N. J., June, 1919. 
Reprinted from Jour. Am. Med. Assn., 1919, Ixxiii, 878-880. 

63 



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64 F. C. MANN AND K. KAWAMURA 

determining the function of the duodenum. The results of the experi- 
ments of this group of early investigators, Pfliiger, Ehrmann, Lauwens, 
Minkowski, Cimoroni, Tiberti, Rosenberg, and Bickel, may be grouped 
under definite headings. All the experiments were performed on dogs, 
with the exception of Pfliiger's; some of his were done on frogs. The 
method of removing the duodenum varied. In no instance was a 
complete, normal reconstruction made. The continuity of the gastro- 
intestinal tract was maintained either by a gastroenterostomy 
(Lauwens, Minkowski, Cimoroni, Tiberti, Rosenberg, Bickel) or by 
an end-to-end anastomosis of the jejunum to the pyloric end of the 
stomach (Ehrmann, Tiberti). The bile and pancreatic secretions 
were taken care of by : 

1. Ligation and complete occlusion of both ducts (Ehrmann). 

2. Cholecystenterostomy and ligation of the pancreatic ducts 
(Minkowski, Tiberti, Rosenberg). 

3. Biliary fistula and ligation of the pancreatic ducts (Cimoroni, 
Tiberti). 

4. Biliary and pancreatic fistulas (Lauwens, Bickel). 

5. Transplantation of both ducts into the stomach (Ehrmann, 
Lauwens) . 

The results of these investigations were not very satisfactory. 
In most instances the animal died shortly after the operation; in 
only a few instances did it recover from the immediate effects of the 
operation. Two of the animals lived two weeks (Lauwens), one three 
weeks (Rosenberg), two four weeks (Minkowski), and one four and 
one-half weeks (Bickel). The final results of some of these experi- 
ments are incomplete. 

Gaultier studied the effect of injury to the duodenal mucosa in 
animals, and Zak' reported observations on the effect of caustics on 
the duodenum in man. 

Matthews studied the effect of various types of experimental 
operations on the duodenum. The duodenum was not actually 
removed in his experiments. Stassoff, in a research on the effect of 
the removal of various portions of the gastro-intestinal tract, also re- 
moved the duodenum. None of his animals in which the duodenum 
was completely removed survived. He was able to keep one animal 
alive in which the portion of the duodenum distal to the entrance 
of the bile duct was resected. 

Since the early investigators of duodenectomy were mainly inter- 



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EFFECTS OF DUODENECTOMY 65 

ested in the relation of the duodenum to pancreatic diabetes, their 
data on the function of the duodenum and the effect of i^ts removal 
are not complete. Most of the animals died shortly after operation, 
and in instances in which the animal survived the method was sub- 
jected to the criticism that not all the duodenal mucosa was removed. 

It should be noted that experiments dealing with the short circuit- 
ing of any particular portion of the gastro-intestinal tract do not 
parallel those in which the same portion has been surgically removed. 
For that reason the experiments of Matthews should be classed with 
those on intestinal obstruction and not of duodenectomy. 

Since our investigation was started, three articles on the subject 
have been published. L. R. and C. A. Dragstedt, McClintock, and 
Chase studied the effect of duodenectomy in two series of dogs. In 
the first series a two stage operation was performed, and in the second 
series a one stage operation. In the first series one animal lived 
twelve days, and in the second, one animal lived three months. None 
of the duodenectomized animals, however, appeared to keep in good 
condition. 

Grey removed the duodenum in three stages, leaving an interval 
of several weeks between each stage. One of his dogs survived all 
three operations (complete removal of the duodenum), and remained 
in perfect health for eight and one-half months. 

Moorhead and Landes also used a three stage operation for the 
removal of the duodenum. They were able to remove the entire 
duodenum and to demonstrate that dogs are able to live in perfect 
health after such a procedure. 

Dragstedt and his collaborators clearly showed that a dog can 
survive duodenectomy, but their work is open to the same objections 
as that of many of the earlier workers, namely: The duodenectomy 
was complicated by a loss of pancreatic, and, in some instances, of 
biliary function. As they suggest, this probably was the cause of the 
failure of their animals to maintain health. The results of Grey, 
one of whose animals lived the longest after duodenectomy, and of 
Moorhead and Landes, prove that duodenectomy is compatible with 
life and perfect health in the dog for relatively short periods. 

Technic of Duodenectomy in Dogs 

In the first experiments we attempted a two stage operation for 
the removal of the duodenum. However, as it was our intention to 

'19-5 



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66 F. C. MANN AND K. KAWAMURA 

make extensive studies of the gastrointestinal tract and the various 
organs after duodenectomy, it was soon seen that by the time the 
second stage of the operation was performed the many adhesions 
would greatly complicate our studies. We attempted to devise a 
one stage operation by combining the two stage operation in one. 
We had a few successes by this method. One animal survived forty- 
one days, but in this case the pancreatic ducts were ligated. 

On account of these unfavorable results a new method was devel- 
oped, and two points were accomplished: (1) The duodenectomy could 
be performed quickly, and (2) all the other involved organs, such as 
the bile duct, both pancreatic ducts, the pancreas and the alimentary 
tract, were restored to correspond as nearly as possible to the normal 
state. Briefly described, the operation consists of four steps : 

1. The dissection of the duodenojejunal fold, the mesoduodenum 
and the lesser omentum, and the ligation of the blood vessels sup- 
plying the upper jejunum and duodenum. 

2. The separation of the pancreas from the duodenum and the 
isolation of the major pancreatic duct and the common bile duct, 
together with the minor pancreatic duct. 

3. The removal of the entire duodenum, with a portion of the 
proximal jejunum and the distal pyloric portion of the stomach. 

4. The implantation of the bile duct and the minor and major 
pancreatic ducts into the jejunum. 

The technic described was developed on the dog, and, with slight 
modifications, it was found to be adaptable to several other species. 
The operation could usually be performed on the dog within from one 
and one-quarter to one and one-half hours, never longer than two 
hours. Several of the animals died as a result of the operative pro- 
cedures before we had developed our technic. Others died from the 
results of intercurrent disease. After our technic was fully developed, 
however, practically all the animals lived. 

Results 

Our results on dogs fully corroborate those of the more recent 
investigators. The animals quickly recovered from the operation and, 
with a few exceptions, have remained in excellent health. Their 
general condition has been good; their weight usually has increased 
or remained stationary. A few of the animals steadily lost weight 



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EFFECTS OF DUODENECTOMY 67 

and strength after the operation. At necropsy, or at exploratory 
operation on these animals, a dilated common bile duct and marked 
infection of the entire biliary tract were usually found. Evidently 
the transplantation of the ducts did not restore a condition sufficiently 
normal to prevent infection. 

Examination of the blood to determine the cell count, hemoglobin, 
carbon dioxid combining power, and hydrogen ion concentration did 
not reveal anything abnormal. 

Examination of the gastro-intestinal tract by the roentgen ray, 
employing a standard barium meal, showed only slight deviation from 
the normal. In some instances, the barium left the stomach sooner 
than in the normal dog, probably because of the loss of the pyloric 
sphincter. At other times, it seemed that the emptying of the stomach 
was slightly delayed and that the course of the meal was a little slower, 
but in each instance this delay was not any greater than in some of the 
normal animals. In general, however, no difference was noted in 
the passage of the barium meal in the duodenectomized and in the 
normal dogs. Roentgenograms of the gastro-intestinal tract appeared 
normal. Future studies may show some effect of duodenectomy on 
the mechanics of digestion, but at present none have been noted. 

Duodenectomy in Other Animals 

Up to this time all experimental duodenectomies, with the excep- 
tion of a few on the frog, had been done on the dog. At the suggestion 
of C. H. Mayo, we attempted to determine the effect of the operation 
on other species, particularly on the herbivorous and omnivorous 
animals. 

The duodenum was removed from the cat. The operation is easily 
performed on this species. It is necessary to transplant only one 
pancreatic duct, that which enters in conjunction with the common bile 
duct, as the other duct is quite small. 

The goat was selected as a suitable type of herbivorous animal. 
The operation is difficult in this species. The duodenum is long; 
the length of intestine removed measured about 90 cm. As the pan- 
creatic duct empties directly into the common bile duct, it is necessary 
to transplant only the latter. The thin walls of the jejunum make the 
anastomosis quite difficult. 

The hog was selected as an omnivorous type of animal. The 



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68 F. C. MANN AND K. KAWAMURA 

removal of the duodenum is very difficult in this species. As the bile 
and pancreatic ducts empty separately, two transplantations must be 
made. For expediency and in order to remove all the duodenum, 
as in operating on the dog, it was found best to section at the duodeno- 
jejunal juncture, invert the end of the jejunum, and unite the jejunum 
slightly more dis tally to the end of the stomach. 

The duodenum was also removed from the monkey (M. rhesus), its 
anatomy being similar to that of man. It is necessary to transplant 
only one duct in this species, since the minor pancreatic duct can be 
ignored. 

We now have ten dogs, one goat, and one hog from which the duo- 
denum has been removed. One of the ten dogs was operated on six 
months ago. All the animals, with the exception of one dog, are in 
good condition. 

Summary 

The investigation was undertaken for the purpose of determining 
the effects of the removal of the duodenum. A one stage operation 
for the removal of the duodenum was developed. The duodenum was 
removed from the dog, cat, hog, goat, and monkey. Careful studies 
on the dog did not reveal any noticeable changes following the duod- 
enectomy. The animals remained in good condition. Examination 
of the blood showed it to be normal with regard to cell counts, hemo- 
globin, carbon dioxid combining power, and hydrogen ion concentra- 
tion. The roentgen ray showed the course of a standard barium meal 
to be practically the same as in a normal dog. Experiments on the 
other species have been too recent to allow conclusions to be drawn, 
but it would seem that the removal of the duodenum in the hog is as 
innocuous as its removal in the dog. No data have been secured to 
show that the duodenum is of great importance in any of the species 
used. Future studies with* particular reference to gastric secretion, 
and so forth, may give more positive results. 

BIBLIOGRAPHY 

1. Bickel, A.: Beobachtungen an Hunden mit exstirpiertem Duodenum. Berl. klin. 
Wchnschr., 1909, xlvi, 1201-1202. 

2. Cimoroni, A.: Sugli effetti dell a resezione totale del duodeno. Sperimentale, 
1908, lxii, 523-584. 

3. Dragstedt, L. R., Dragstedt, C. A., McCIintock, J. T., and Chase, C. S.: Extir- 
pation of the duodenum. Am. Jour. Physiol., 1918, xliv, 584-590. 



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EFFECTS OF DUODENECTOMY 69 

4. Ehrmann, R.: Ubcr den Einfluss der Ausschaltung des Zwolffingerdarms auf die 
Zuckerausscheidung und iiber sein Beziehung zum experimentellen Pankreasdiabetes. 
Archiv. f. d. ges. Physiol., 1907, cxix, 295-296. 

5. Gaultier, R.: Quoted by Pfliiger. 

6. Grey, E.G.: Demonstration of a duodenectomized dog. Bull., Johns Hopkins 
Hue»p. 1918, xxix, 152. Duodenectomy — its effect upon the life of an animal. Trans- 
plantation of the pancreatic duct. Surg., Gynec. and Obst., 1919, xxviii, 86-42. 

7. Lauwens, R.: Exstirpation des Duodenum betreffender Brief an den Herausgeber. 
Archiv. f. d. ges. Physiol., 1907, cxx, 623-625. 

8. Matthews, S. A.: One of the functions of the duodenum. Jour. Am. Med. 
Assn., 1910, Iv, 295-295. 

9. Minkowski, O.: Die Totalexstirpation des Duodenums. Arch. f. exper. Path. u. 
Pharmakol., 1908, lviii, 271-288. Also: Deutsch. med. Wchnschr., 1908, xxxiv, 45. 

10. Moorhead, J. J., and Landes, H. E. : Duodenectomy. Jour. Am. Med. Assn., 
1919, Ixxii, 1127-1129. 

11. Pfliiger, E.: Untersuchungen iiber den Pankreasdiabetes. Arch. f. d. ges. 
Physiol., 1907, cxviii, 267-820. Durch neue Experimente gestutzte Bemorkungen zu 
den jungsten Arbeiten iiber den Duodenal-diabetes des Hundes. Arch. f. d. ges. 
Physiol., 1908, cxxiii, 323-328. Ueber die durch Resection des Duodenums bedingten 
Glykosurien. Arch. f. d. ges. Physiol., 1908, cxxiv, 1-28. 

12. Rosenberg, S.: Zur Frage des Duodenal-diabetes. Arch. f. d. ges. Physiol., 
1908, cxxi, 358-362. 

13. Stassoff, B.: Experimentelle Untersuchungen liber die kompensatorischen Vor- 
gange bei Darmresektionen. Beitr. z. klin. Chir., 1914, lxxxix, 527-589. 

14. Tiberti, N. : Intorno alia estirpazione totale del duodeno. Sperimentale, 1908, 
Ixii, 479-495. 

15. Zak, E.: Glykosurie bei Veratzungen des Duodenums. Wien. klin/Wchnschr.. 
1908, xxi, 82-83. 



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THE ROUTINE MANAGEMENT OF DUODENAL ULCER 

CASES* 

W. S. LEMON 



For several centuries physicians have known of the presence of 
ulcer in the stomach, but it is only within the last hundred years that 
the condition has been known to exist in the duodenum (Travers). 
Abercrombie, in 1830, noticed that distress came not with food but 
with its passing from the stomach. Sibson, in 1857, discussed the 
early treatment. Bucquoy, in 1887, was able to make a diagnosis 
before hemorrhage or perforation and consequent death had revealed 
the cause and the nature of the ailment. From that time, stimulated 
by Moynihan's report, in 1900, of his first operation for duodenal ulcer* 
by Weir's presidential address on perforating ulcer of the duodenum 
to the American Surgical Association in the same year, and by Mayo's 
report, in 1904, the advance in knowledge of the subject was rapid 
and the interest all absorbing. It has been found that ulcer of the 
duodenum has a definite symptomatology and can be diagnosed with 
much exactness by a study of the anamnesis alone. Other methods 
of diagnosis have been perfected and have become so reliable that but 
few cases presenting symptoms — a few do not present symptoms — are 
mistaken. 

The examination of a patient complaining of trouble referable to 
the stomach must be made most carefully. The study of the case 
demands the care commensurate with its importance, and should 
occupy a period of at least three days. The first day a thorough history 
is taken, not by help of "leading questions," but first by allowing the 
patient to talk freely of his complaint, then by direct questioning and, 
finally, by repeated review. This is done daily until all the facts are 
obtained and have been set down chronologically. A complete 
physical examination is also carefully made the first day. The blood 
pressure is taken to detect evidence of arteriosclerosis, which in the 

* Presented before the Forty-fifth Annual Meeting of Oregon State Medical Asso- 
ciation, Portland, June, 1919. 

Reprinted from Northwest Med., 1919, xviii, 179-184. 

70 



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MANAGEMENT OF DUODENAL ULCER CASES 71 

aged may cause abdominal pain, and the temperature and pulse are 
noted for evidence of infection. The pupillary reflexes, the size and 
equality of the pupils, the presence or absence of scars, the movements 
of the eyeballs, the condition of the nose, the presence of oral sepsis 
or of infected tonsils, the condition of the ears, especially with regard 
to bone conduction because of its bearing on luetic infection, are noted, 
and a systematic examination is made of the glands, the thorax, the 
abdomen, and of the pelvis, either by the vaginal or the rectal route. 
The weight, strength, tremors, rigidity of muscles, superficial and 
deep reflexes, sensation and station are observed and recorded. In 
cases of duodenal ulcer anatomic thinking is particularly necessary so 
that no detail may be missed, because a large number of seemingly 
unrelated factors may produce symptoms referable to the stomach. 

On the first day the blood count is taken, and the sputum and the 
urine examined. If there are any findings on physical examination 
of the lungs, the chest is roentgenographed. Other special examina- 
tions are made, such as the result of the general examination and study 
may indicate. 

On the second day a Wassermann test is made, and the stool is 
examined for parasites, pus, blood and occult blood by both the Weber 
and benzidin methods. The latter is a confirmatory test and is 
not looked on as essential, but when positive it adds to the evidence 
required. 

The diagnosis is usually made on the third day. Confirmation 
may be accomplished in two ways: first, by the reaction to medical 
management and by continuing the study of the stool and of the 
gastric contents after meals by means of the Ewald or motor tests, 
and, second, by gastric analysis followed by fluoroscopic study and ex- 
amination of roentgenographs plates of the patient. The latter is the 
method most used; it has proved entirely satisfactory. The remainder 
of the third day is devoted to the correlation of the impressions gained 
from the history and the observations made at examination with the 
findings of the laboratories and the evidence of the roentgenograms. 
Only by such correlation can a differential diagnosis be worked out and 
finally a certain diagnosis reached. Cheney endorses the complete 
and detailed examination; he says, "The old diagnostic combination 
of characteristic history, negative physical findings, and stomach 
contents showing hyperacidity can no longer be depended upon." 
Carman summarizes his opinion regarding such diagnosis in the words, 



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72 W. S. LEMON 

"In short, I believe that no diagnosis can be too strongly fortified, 
and that any gross discordance between the findings from all sources 
should make the examiner cautious in his opinions." 

The patient whose several examinations agree perfectly in deter- 
mining duodenal ulcer will be in early adult or middle life, more often 
a man than a woman. He will tell of trouble lasting for from ten 
to fifteen years, a distress coming on insidiously in "spells" of from a 
week's to a month's duration, at first rather slight, later impressed on 
his memory by increasing frequency and severity. The spells usually 
appear in the spring or the fall or when the patient is under heavy 
stress of physical or mental work and they may be aborted by rest. 
Frequently the patient will say that his trouble is without discoverable 
cause, certainly not due to any particular kind of food, indeed that 
food during the inactive periods can be taken without discomfort, 
that it does not cause pain but rather eases the pain during the attacks, 
and that it is the emptiness of the stomach which produces his distress. 
Many patients volunteer the information that food brings relief and 
that soda or hot water or lavage produces the same result. Later in 
the course of the cycle pains come on at two or three o'clock in the 
morning, and, because they are relieved by food, the patient keeps a 
cracker or a glass of milk at his bedside. He gives the usual symptoms 
of hyperacidity, such as heartburn, belching, waterbrash, nausea, and 
often pain before vomiting which continues during the spell; within 
a few months after each attack there is a return to normal strength 
and vigor. The patient may speak of complications such as faintness 
and giddiness coming on suddenly with succeeding pallor and accom- 
panied by black stool and occasionally by hematemesis, of sharp and 
very severe griping pains, indications of early perforation or of the 
continuous distress of obstruction with cramping pain and frequent 
vomiting, due either to edema and swelling or, when the trouble has 
persisted for a long time, to scarring and narrowing of the pylorus. 
Such a history, combined with a physical examination showing tender- 
ness in the epigastrium or just to the right of the midline, rigidity of 
rectus and increased epigastric reflex, a report of hyperacidity, 
excessive motility on fluoroscopic examination and deformity of the 
duodenal cap, makes a diagnosis of ulcer almost certain. 

I have summarized, in Table 1, the results of observations made by 
Moynihan, Graham, Mayo, Eusterman, Beckman, and myself. These 
points in differential diagnosis are applied daily in my clinical work. 



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MANAGEMENT OF DUODENAL ULCER CASES 73 

Only after consideration of the results of clinical, laboratory, and 
x-ray examinations can it be determined whether medical or surgical 
means should be advised. In a most painstaking and minute manner 
Sippy has outlined his method of medical management, worked out 
by long and extensive clinical experience at the Presbyterian Hospital 
in Chicago. He gives only six indications for surgical intervention. 

1. Secondary carcinoma. 

2. Perforation into the free peritoneal cavity. 

3. Pyloric obstruction of high grade due to indurated tissue nar- 
rowing that fails to yield to medical management. 

4. Perigastric abscess. 

5. Hour-glass stomach. 

6. Hemorrhages. 

Sippy states that the cases of pyloric obstruction that do not yield 
to medical treatment embrace only 10 per cent of the cases of obstruc- 
tion, that the remaining 90 per cent are due to "pyloric spasm, acute 
inflammatory swelling and in some instances local peritonitis, and that 
the obstruction disappears during the first two or three weeks under 
the influence of medical treatment." Operation is only infrequently 
necessitated by hemorrhage associated with duodenal ulcer. All 
cases not included in one of the six classes named are treated by medical 
management, the essentials of which are the maintenance of the ab- 
sence of acid and consequently the prevention of corrosion. The 
details of the treatment, that is, the frequent meals, the alkali interval, 
the aspiration to determine acidity, the daily stool examinations, and 
the long preliminary confinement to bed, followed by many weeks of 
rigid adherence to the management, are too well known to require 
further comment. Sippy finds that: 

1. Patients under medical treatment do well subjectively. 

2. The management must be long continued and repeated. 

3. Blood will disappear from the stool within ten days except in 
cases of malignancy. 

4. The pains of obstruction, the nausea, and vomiting disappear 
within a few days except in cases of cicatricial stenosis. 

5. Acidity can be maintained at whatever level is desired. 

Since the surgical examination of these cases has proved that they 
heal spontaneously only in rare instances, the disadvantages in such 
routine treatment are manifest. In this connection Moynihan 
states, "Relief of an attack in a case of chronic duodenal ulcer is easy; 



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74 



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MANAGEMENT OF DUODENAL ULCER CASES 



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a cure of the condition by medical means, 
is, I believe, almost impossible." And again, 
" The lesion found is of such a nature that any- 
thing other than surgical treatment is not worth 
considering. It is safer, speedier, and more 
certain than any other mode of treatment." 

After a period of serious symptoms last- 
ing for some weeks the patient with duode- 
nal ulcer may have complete relief, and yet, 
if operated on during the quiescent period, 
the ulcer will almost regularly be found open 
and unhealed. The supposed cures of chronic 
ulcers of the stomach and duodenum may be 
compared with the supposed cures following 
each attack of recurring appendicitis or gall- 
stone disease. 

The unprejudiced observer, I believe, must 
come to the conclusion that operative relief 
in cases of calloused ulcers of the stomach 
and duodenum is indicated after a reasonable 
amount of medical treatment has failed to 
produce a permanent cure. It has been our 
experience at the Mayo Clinic that patients 
who have grown weary of being so often 
"cured" medically come for surgical help. 
At operations performed in many cases within 
only a few weeks of the completion of a rigid 
medical management, and at many operations 
performed during the remission of symptoms, 
an active ulcer was found. The remission in 
the latter case represents the "normal" rest- 
ing stage; in the former it is artificially pro- 
duced. It is our practice in the very recent 
cases to ask the patient to undergo medical 
treatment and to give the ulcer the best op- 
portunity possible for spontaneous healing. 
Long standing ulcers, we believe, do not heal 
and should be surgically treated to remove 
the danger of hemorrhage and of perforation. 



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78 W. S. LEMON 

A comparison of the results of medical and surgical treatment 
may be gained from the following deductions : 

1. Eighty-one per cent of patients with duodenal ulcer operated 
on at the clinic were so much relieved that they could be considered 
cured, and 10 per cent were markedly benefited (Graham). 

2. Acidity is reduced by the mechanical hooking up of the jejunum 
with the stomach, because it allows the alkaline secretion of the duode- 
num to flow into the stomach and neutralize its acidity. (In the 
series of 200 cases I have studied this has been found to be universal 
and the average reduction in total acidity 39 per cent, in free hvdro- 
chloric acid 46 per cent). 

3. If patients are to remain well they must have focal infections 
removed. Patients who are not improved or those with gastro- 
jejunal ulcer, except those in whom operative technic has provided 
a mechanical cause (Mayo, Carman and Balfour), usually show a 
high grade of neglected oral sepsis, even when most urgent advice 
had been given at the time of operation. 

4. Operation reduces to the minimum the danger of perforation 
and of hemorrhage. 

Because there are patients who do not improve when treated only 
by surgery, every patient should be advised with regard to postopera- 
tive care until permanent cure is assured. Acidity has been reduced 
mechanically; it may be kept at a minimum by medical management. 
Every patient should be informed after operation as to proper diet, 
the basis of which should be milk, cream, eggs, cereals, vegetables, 
purees, gelatin, scraped beef, bread and butter, jellies, custards, and 
creamed foods; later other lean meats and broths may be added. 
The patient's weight must be watched so that loss may be prevented 
and diet kept up to the bodily requirement. By such dietetic control 
and by the use of alkali in suitable doses the acidity can be accurately 
controlled when only three meals a day are taken. It is my practice, 
however, to advise a morning and an afternoon lunch, consisting 
usually of a glass of milk and a cracker, at least during the firs t few 
weeks of canvalescence. This is productive of good results and will 
increase the chances of the surgically treated ulcer patients to regain 
and to maintain normal health. Only patients who were not given 
the usual advice have complained postoperatively. Operation for 
duodenal ulcer cures in most cases, and it improves in almost all. 
Clinicians must do their part by postoperative advice to help obtain, 
the best results from the operation. 



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MANAGEMENT OF DUODENAL ULCER CA8ES 79 



BIBLIOGRAPHY 

1. Abercrombie, J.: Pathological and practica research on diseases of the stomach. 
2 ed. Edinburgh, Waugh and Innes, 1830, 424 pp. (Quoted by Moynihan.) 

2. Beckman, E. H.: The differential diagnosis of lesions of the stomach and duo- 
denum. Lancet-Clinic, 1916, cxv, 242-245. 

3. Bucquoy: Arch. gen. de m6d., 1887, i; 398. (Quoted by Moynihan.) 

4. Carman, R. D. : Roentgen signs of gastrojejunal ulcer — some suggestions as to 
technic of examination — report of two cases. Am. Jour. Roentgen., 1915, ii, 749-754; 
Spasm of the stomach and duodenum from a roentgenologic point of view. Jour. Am. 
Med. Assn , 1916, Ixvi, 1283-1288; The roentgenologic diagnosis of duodenal ulcer. 
Am. Jour. Roentgen., 1916, iii, 252-256. 

5. Carman, R. D. and Balfour, D. C. : Gastrojejunal ulcers. Theii roentgenologic 
and surgical aspects. Jour. Am. Med. Assn., 1915. lxv, 227-232. 

6. Cheney, W. F.* Differential diagnosis of peptic ulcer. Jour. Am. Med. Assn., 
1919, lxxii, 1429-1432. 

7. Eusterman, G. B. : Incidence and diagnosis of complicating factors in gastric and 
duodenal lesions. Results in 1800 cases operated upon. Am. Jour. Gastro-Enterol., 
1913-1914, iii, 111-118; Chronic gastric disturbances: Differential diagnosis. Journal- 
Lancet, 1914, xxxiv, 460-464; The essential factors in the diagnosis of chronic 
gastric and duodenal ulcers. Jour. Am. Med. Assn., 1915, lxv, 1500-1503; Gastric 
and duodenal ulcer; New York State Jour. Med., 1917, xvii, 88-94. 

8. Graham, C. : Diagnosis between duodenal ulcer and gallstone disease. Jour. Am. 
Med. Assn., 1907, xlviii, 515-517; Prominent symptoms in the diagnosis of, gastric 
and duodenal ulcers. Jour. Am. Med. Assn., 1908, li, 651-653; Diagnosis of gastric 
ulcer with differential diagnosis. 111. Med. Jour., 1909, xvi, 137-143; Notes on gastric 
and duodenal ulcers. Boston Med. and Surg. Jour., 1915, clxxiii, 543-547. 

9. Mayo, W. J. : Duodenal ulcer, a clinical review of fifty-eight operated cases with 
some remarks on gastrojejunostomy. Ann. Surg., 1904, xl, 900-908. The contribu- 
tions of surgery to a better understanding of gastric and duodenal ulcer. Ann. Surg., 
1907, xlv, 810-817; Chronic ulcer of the stomach and duodenum. St. Paul Med. 
Jour., 1908, x, 331-338; Ulcer of the duodenum, with report of two hundred and 
seventy-two operations. Jour. Am. Med. Assn., 1908, li, 556-558; Gastrojejunal 
ulcers (pseudojejunal ulcers). Surg., Gynec. and Obst., 1910, x, 227-229; Diseases 
of the stomach and duodenum from a surgical standpoint. St. Paul Med. Jour., 1911, 
xiii, 1-9; Ulcer of the stomach and duodenum with special reference to the end results. 
Ann. Surg., 1911, liv, 313-320; Pathologic data obtained from ulcers excised from the 
anterior wall of the duodenum. Ann. Surg., 1913, lvii, 691-694; Recurrences of ulcer 
of the duodenum following operation. Boston Med. and Surg. Jour., 1914, clxx, 149-151. 
Chronic ulcers of the stomach and duodenum. Ann. Surg., 1914, lx, 220-226; Chronic 
duodenal ulcer. Jour. Am. Med. Assn., 1915, Ixiv, 2036-2040. 

10. Moynihan, B. T. A. : Duodenal ulcer. 2 ed. Philadelphia, Saunders, 1917, 486 pp. 

11. Sibson, F.: Cases of diseases of the stomach. Brit. Med. Jour., 1857, i, 82. 

12. Sippy, B. W. : Gastric and duodenal ulcer. In: Musser and Kelly, Eds. A hand- 
book of practical treatment. Philadelphia, Saunders, 1917, iv, 610-628. 

IS. Travers, A.: Additional observations. Med.-Chir., Tr.. 1817, viii, 231. 
14. Weir, R. F. : Perforating ulcer of the duodenum. Boston Med. and Surg. Jour , 
1900, cxlii, 453-463. 



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SURGICAL TREATMENT IN THE BLEEDING TYPE OF 
GASTRIC AND DUODENAL ULCER* 

D. C. BALFOUR 



The surgical treatment of uncomplicated benign lesions of the 
stomach and duodenum has reached a high state of efficiency and 
standardization. The various complications, however, which may 
develop in direct connection with gastric and duodenal ulcer, such as 
acute and chronic perforation, obstruction, deformity, malignant 
degeneration, and hemorrhage, present added problems to the surgeon; 
one of the most important of these is hemorrhage. 

Gastric hemorrhage has been the occasion of more confusion in 
diagnosis, uncertainty in therapeutic indications, and irrationality 
in treatment, both medical and surgical, than p erhaps any other gastric 
condition. The number of cases seen in which an erroneous inter- 
pretation of symptoms has led to incorrect suggestion for treatment, 
resulting in failure to protect the patient against further hemorrhage, 
illustrates the necessity of persistent study of the subject. This 
paper is concerned chiefly with two groups of cases: first, those in 
which operation has proved unsatisfactory because of error in attribut- 
ing the bleeding to a lesion which is not present, and second, those in 
which the surgical procedure carried out has failed to obviate further 
hemorrhages, even though a correct diagnosis has been made. 

A study of these groups disclosed certain facts which indicated 
that it should be possible to decrease the incidence of such failures; 
in the first group, by more accurate preoperative diagnosis, with better 
interpretation of operative findings; in the second group, by the addi- 
tion of certain specific measures to the standard surgical procedures 
applicable to benign lesions of stomach and duodenum. 

The first group of cases, those in which no intrinsic lesion is present, 
not only is large but also includes a variety of conditions which may be 

* Presented before the Section on Obstetrics, Gynecology and Abdominal Surgery at 
the Seventieth Annual Session of the American Medical Association, Atlantic City, 
June, 1919. 

Reprinted from Jour. Am. Med. Assn., 1919, lxxiii, 571-575. 

80 



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GASTRIC AND DUODENAL ULCER 81 

associated with hematemesis. Some of these conditions do not fall 
within the field of the surgeon, but there are other conditions which 
can be eradicated by surgical means, and this group is so important 
that I shall review briefly a representative example, a case illustrating 
the diagnostic error of presupposing gastric ulcer because of hema- 
temesis, and of following the error by carrying out a routine operation 
on the stomach designed to cure this imaginary ulcer: 

A man (Case 132411), aged 55, came to the clinic, June 5, 1915, 
because of recurring hematemesis. In some of the attacks the patient 
had been almost exsanguinated. The hemorrhages had begun in 
January, 1914, without a previous history suggestive of a causative 
factor; in July, 1914, a gastro-entei ostomy was performed at hia 
home; he was told that an ulcer was found at the pylorus. Some 
weeks after the operation a hemorrhage occurred similar to those he 
had had before the operation, and between that time and his regis- 
tration in the clinic he had had several distinct gastric hemonhages, 
the last severe one occurring in February, 1915. There were no 
typical symptoms nor physical or laboratory findings to establish a 
diagnosis, but the patient's condition and history were such as to 
make further exploration imperative. 

In July, 1915, 1 explored and found a patent and well functioning 
gastroenterostomy. Palpation revealed no induration in stomach 
or duodenum, and no visible signs of ulcer, nor did careful inspection 
through a large opening in the anterior wall of the stomach show 
any evidence of an active or healed ulcer at the anastomosis or in 
the stomach or duodenum. Exploration of the biliary tract disclosed 
a slight thickening of the walls of the gallbladder through which the 
yellowish spots on the surface of the mucous membrane which indi- 
cate a cholecystitis of the "strawberry" type could clearly be seen. 
The pancreas, too, showed very distinct changes, being considerably 
enlarged and nodular. This fact, the gallbladder findings, and past 
experience in similar cases, seemed a clue to the cause of the hema- 
temesis. There were no recognizable changes in the liver, and general 
exploration was negative . A cholecystectomy was performed because 
in our experience with cholecystitis, with or without stones, associ- 
ated with pancreatitis, and without jaundice, this has seemed the 
operation of choice. A well defined chronic catarrhal cholecystitis 
of the most typical "strawberry" type was found. The patient 
made an uneventful recovery and has had no hemorrhage since. 

'19-6 



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82 



D. C. BALFOUR 



Similar cases in which the appendix, spleen or liver is the basic focus 
are not infrequently seen. 

The first question, then, to demand a decision in cases of gastric 
or gastro-intestinal hemorrhage concerns the cause of the hemorrhage. 
Fortunately, in the majority of cases careful history taking, associated 
with expert interpretation of roentgen-ray findings, will usually 
determine whether or not an ulcer is present. If the evidence does 
not support a diagnosis of ulcer, but indicates disease in some organ 
in the abdomen, such as the gallbladder, pancreas or appendix, it 






'IE 



is 



l /./ 






W 

/ 

■ | 

Fig. 34. — Shaving of thickened musculoperitoneal coats. 

must not be forgotten that gastric hemorrhage may be due to such 
extrinsic causes. The spleen and liver particularly should be kept in 
mind as causative factors, for it has been proved that either the spleen 
or the liver or both can be the cause of most serious gastro-intestinal 
bleeding without showing any changes that are recognizable in our 
present state of knowledge. The group of cases in which an undoubted 
gastric hemorrhage has occurred but in which the symptoms or physical 
findings are insufficient to lead to a positive diagnosis either of ulcer 
or extrinsic trouble requires, therefore, the most serious consideration 
as to whether operation should be undertaken. Fortunately, symp- 
toms are usually associated with such hematemesis, and, though 
obscure, justify an exploration, and although doubt may exist as to 



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GASTRIC AND DUODENAL ULCER 



83 



any satisfactory explanation being found to account for the hemateme- 
sis, frequently pathologic conditions extrinsic to the stomach are found 
which, when eradicated, secure permanent protection against further 
hemorrhage. In hematemesis unassociated with abdominal symptoms 
or findings, and in which it is not possible to establish a diagnosis, 
operative interference should, as a rule, be advised against. 







Ga-st^ 



Stom.ac 



m 



JC^ 



Fig. 35. — Probe introduced through the site of chronic perforation. 

The group of cases, however, to which I particularly refer is that 
group in which recurring gastric hemorrhage has been caused by a 
chronic gastric or duodenal ulcer. Our records show that 25 per cent 
of gastric ulcers and 20 per cent of duodenal ulcers have been compli- 
cated by one or more gross hemorrhages. In the earlier days of gastric 
surgery the operation of gastro-enterostomy proved to be so efficient 
in a large majority of benign lesions of the stomach and duodenum 
associated with hemorrhage that the realization came rather slowly 
that at least some of the failures to obtain a complete cure, including 
protection against further hemorrhage, could be attributed to the 



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84 



D. C. BALFOUR 



fact that direct attack on the ulcer was not added to the indirect 
therapeutic measure of gastroenterostomy. The recognition of the 
danger of malignant degeneration in gastric ulcer gave the first impetus 
to the practice of combining gastroenterostomy with the radical 
excision or destruction of such ulcers. The advisability of such a 
principle is now well established. 

It has, therefore, become quite evident that in the surgical treat- 
ment of a gastric or duodenal ulcer which has been the cause of hemor- 
rhages, some direct attack on the ulper is most important. The 
necessity for this has become apparent to us because of the fact that a 
number of our own patients with duodenal or gastric ulcer had failed 
to secure, by gastroenterostomy alone, protection against further 
bleeding. Apparently rare as such failures were, they nevertheless 
formed in the aggregate a group which called for an investigation as 
to the possibilities of reducing the number of such recurrences. A 
concise compilation of such cases illustrating the incidence of hemor- 
rhage as a late postoperative complication may be found in the accom- 
panying tables. The cases chosen for study were those in which 
operation was performed in the Mayo Clinic during the twelve year 
period between January, 1906, and January, 1918. 

A study of Table 1, which represents the percentage of hemorrhages 
following operations for duodenal ulcer, shows that 12.7 per cent of 

Table 1. — Hematemesis in Cases of Duodenal Ulcer in Which Operation was 

Done 

Jan. 1, 1906, to Jan. 1, 1918 



Cases, No. 



Per Cent 



Operative 
Mortality 
irom Ail 
Causes, 
Per Cent 



Total number . 2875 - 1.6 

Patients having hemorrhage before operation . . 58S 20 + j 1 + 

Patients having hemorrhage before operation I 

heard from I 494 86 .0 I 

Patients reporting hemorrhage after operation 63 12 . 7* ! 

Patients reporting hemorrhage after operation but | : 

none before 20 I 0.9 

! i • 

* Or 2 per cent of the total number. 

the patients who had hemorrhages before operation had hemorrhages 
after operation, and in two instances the hemorrhages were sufficient 



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GASTRIC AND DUODENAL ULCER 85 

to cause death. Twenty patients (0.9 per cent) in the group who had 
not reported hemorrhages before operation had hemorrhages following 
operation. Eighty-three patients, 2.8 per cent of the total number 
operated on, had hemorrhages following operation. 

Fifteen patients (8 per cent) with gastric ulcer report hemorrhage 
after operation who had had hemorrhage before, and two patients 
(0.3 per cent) had hemorrhage who had not had hemorrhage before 
operation. Seventeen patients, therefore, suffered from hemorrhage 
after operation, a percentage of 1+ of the total member of gastric 
ulcers operated on. 

A comparison of the figures in Tables 1 and 2 shows that the 
incidence of hemorrhage in duodenal ulcer following operation is 
definitely higher than the incidence in gastric ulcer, notwithstanding 
the fact that there is a greater tendency for gastric ulcer than for 
duodenal ulcer to be complicated by bleeding. This important fact, 
namely, the difference in operative results in gastric and duodenal 
ulcers, may be largely attributed to essential differences in operative 
technic. 

The radical treatment of gastric ulcer was originally due to the 
recognition of the fact that an ulcer on the gastric side of the pylorus 
holds unquestionable possibilities of becoming malignant. Excision 
of such ulcers either by knife or cautery was, therefore, performed 
whenever possible by surgeons whose experience was sufficient to 
make them appreciate the necessity of this treatment. Such radical 
measures necessarily carry a higher operative mortality, but the 
avoidance of such mortality by simpler operative measures means 
a marked increase in ultimate morbidity and mortality. 

In duodenal ulcers, however, radical treatment was not necessary 
because of this possibility of malignant degeneration or of disabling 
complications, and the indirect method of treatment by gastroente- 
rostomy proved to be sufficient in a high percentage of cases to relieve 
the patient of the symptoms of which he complained. The more 
frequent occurrence of hemorrhage after operation for duodenal ulcer 
than for gastric ulcer is apparently due to this difference in operative 
procedure, and the following facts bear out such a statement: 
In not one of the 83 cases in which hemorrhages occurred after 
operation for duodenal ulcer was the combined operation of excision 
of the ulcer with gastroenterostomy carried out, and with the excep- 
tion of 8 cases in which various types of pyloroplasties were per- 



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86 



D. C. BALFOUR 



formed, in every case a gastroenterostomy alone was performed. 
This fact is significant particularly when one compares the results 
of the established methods of excision and gastro-enterostomy in 
gastric ulcer in which, although the tendency to hemorrhage had been 
greater* a much smaller percentage of bleeding followed operation. 




Fig. 36. — Peritoneal surface of ulcer prepared for application of cautery. 

The combined procedure of excision and gastro-enterostomy was 
carried out in only one of the 17 cases of gastric ulcers in which 
there was bleeding after operation. These facts can only mean that 
the methods of direct attack combined with gastro-enterostomy which 
are used in the treatment of gastric ulcer are a source of protection to 
the patient against further hemorrhage. 



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GASTRIC AND DUODENAL ULCER 



87 



Table 2. — Hematemesis in Cases op Ulcer of the Stomach in Which Operation 

was Done 



Cases, No. 



Operative 

I Mortality 

Per Cent ; from AU 

Causes, 

i Per Cent 



Total number 

Patients having hemorrhage before operation 

Patients having hemorrhage before operation 

heard from 

Patients reporting hemorrhage after operation . . . 
Patients reporting hemorrhage after operation but 

none before 



863 




3+ 


222 


1 25.8 


4.8 


180 


i 
1 81+ ! 




15 


8.0* ; 




2 


0.3 ! 





* Or 1 -|- per cent of the total number. 

Another point brought out in the study of these cases is that in the 
majority of those patients who had bleeding after operation, the opera- 
tion relieved all other symptoms, so that the recurrence of the complica- 
tion of hemorrhage was the only feature which marred an otherwise 
perfect result. This fact is difficult to explain. It raises the question, 
for example, whether the hemorrhage actually comes from the site 
of the symptomless ulcer. The fact that the mucous membrane can 
bleed when no visible lesion is present, and that recurring hemorrhages 
from the stomach may take place without any demonstrable changes 
either in the stomach or in any other organ, throws some doubt on 
the assumption that all such recurrences have their origin at the site 
of the ulcer. But the fact remains that in the majority of cases in 
which we have reoperated, radical treatment of the ulcer area obviated 
further hemorrhages. 

Our gradual realization of these facts, particularly when we found 
that 12 per cent of duodenal and 8 per cent of gastric ulcers which 
had been the source of bleeding before operation bled after operation, 
led to a thorough search for some means of lowering the incidence of 
these failures. From a study of our own cases it was perfectly evident 
that gastroenterostomy alone, as I have pointed out, is insufficient 
protection against further hemorrhages, and that excision combined 
with gastroenterostomy has given almost total protection. The 
problem resolves itself, therefore, into one which concerns the safest 
method of accomplishing a radical excision in the majority of cases. 
Various suggestions have been made and carried out at different times. 



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88 



D. C. BALFOUR 



Ligation of the vessels in the circumference of the ulcer, a procedure 
highly recommended by Woolsey, devitalization by constricting 
suture, pyloric exclusion of von Eiselsberg, and excision have all been 
tried. Unfortunately, under certain circumstances knife excision is 




Duodenum, 



Fio. 37.- 



cautery puncture over a small duodenal ulcer; b, completed operation; 
omentum implanted over site of closure. 



a formidable technical procedure and one at which even the experi- 
enced surgeon will wisely hesitate. In a search for some method which 
will be at the same time radical, safe and applicable in the largest 
number of cases, we have adopted the actual cautery as meeting these 
requirements. 



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GASTRIC AND DUODENAL ULCER 



89 



Technic 

The. technic for the use of the cautery in the bleeding type 
of gastric ulcer differs in no particular from that used in the ulcer 
which has not been associated with bleeding; it may be briefly'described 
by stating its important features. 2 Probably the most important 
point in the technic is the exposure of the peritoneal side of the ulcer, 
and, in a great many instances, as we have recently demonstrated, a 
close shaving of the gastrohepatic omentum (Fig. 34) with a portion of 



*** **#*\ 














~> 



Fio. 38. — Ulcer of the duodenum apparently healed but the cause of recurring hemor- 
rhage. Silk suture which had been placed at a previous operation. 

the thickened peritoneal coat will disclose the minute opening which 
marks the site of chronic perforation. In many cases a probe may 
be introduced (Fig. 35) through this tract and used as a guide in 
introducing the cautery (Fig. 36). This observation seems important 
because it shows the frequency with which this perforation can be 
demonstrated, and that chronic perforation occurs in practically all 
chronic ulcers. Knowing from palpation the size of the crater of the 



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90 



D. C. BALFOUR 



ulcer, the cauterizing is maintained until an opening as large as the 
crater is made. In this way, as I have pointed out in previous articles l 
any malignant cells within an area of £ cm. of the cautery point are 
killed, and the danger of cancer-cell grafting, which is always present 
in knife excision, is avoided. The opening is subsequently closed with 
fine chromic catgut, and with reinforcing sutures of silk. 




w^h. 



Fig. 39. — a, entire scarred area excised with cautery; b, transverse closure of cauterized 
opening by first row chromic catgut. 

Cauterization is simpler in duodenal than in gastric ulcers, as the 
duodenal ulcer is usually in direct view and is rarely protected by any 
surrounding tissue; moreover, the crater of the ulcer is often very 
small, so that only puncture of the ulcer is required (Fig. 37 a and b). 
The cautery in duodenal ulcer was first employed in ulcers of the bleed- 
ing type, but lately it has seemed advisable to destroy, in this manner, 



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GASTRIC AND DUODENAL ULCER 



91 



practically all duodenal ulcers which are readily accessible (Figs. 38, 
39 a and 6, and 40). 




Fig. 40. — a, cauterized opening closed by row of catgut; 6, closure reinforced by a 
returning second continuous suture. 



SUMMARY 

The points which I desire to emphasize are : 

1. Hemorrhage following operations for both gastric and duodenal 
ulcer is of sufficient frequency (2 per cent in duodenal ulcer and 1 + 
per cent in gastric ulcer) to warrant a revis on of operative methods 
in such cases. 



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92 D. C. BALFOUR 

2. Gastroenterostomy or pyloroplasty alone does not always 
protect against further hemorrhages, while excision of the ulcer and 
gastroenterostomy gives almost total protection. 

3. Excision by cautery combined with gastroenterostomy is the 
most satisfactory method in the majority of cases of minimizing the 
possibility of recurrence of hemorrhage in all ulcers which have been 
associated with hemorrhages, and similar treatment seems advisable 
in both gastric and duodenal ulcers which have not exhibited such a 
complication. 

BIBLIOGRAPHY 

1. Balfour, D. C: Treatment by cautery of gastric ulcer. Surg., Gynec. and 
Obst., 1914, xix, 528-530. 

2. Balfour, D. C: Cautery excision of gastric ulcer. Ann. Surg., 1918, lxvii, 
725-731. 

3. von Eiselsberg, F. A.: The choice of the method of operation in the treatment 
of gastric and duodenal ulcer, with a review of my experience accumulated in the 
past ten years. Surg., Gynec. and Obst. 1914, xix, 555-563. 

4. Woolsey, G.: The surgical aspects of gastric hemorrhage. New York Med. 
Jour., 1918, cvii, 395-398. 



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LIFE EXPECTANCY OF PATIENTS FOLLOWING OPER- 
ATIONS FOR GASTRIC AND DUODENAL ULCER* 

D. C. BALFOUR 



Efficiency in the surgical treatment of many diseases has been 
measured in the past by operative mortality, and by the permanency 
of relief which the patient has secured by operation. With the gradual 
development of surgical technic, and our increasing knowledge of 
surgical indications, operative mortality and relief of symptoms have 
been so favorably influenced that they have now in many fields appar- 
ently reached their limit of development. It is also true, however, that 
in all diseases life expectancy can be said to be the major considera- 
tion with the patient, and yet this consideration of pre-eminent 
interest to the patient has not received the study which it deserves, 
particularly in those diseases in which operation is conducted pri- 
marily for the relief of symptoms. 

Diseases of the gastro-intestinal tract stand out most prominently 
as illustrations of this fact. With the advent of operations such as 
gastroenterostomy, in which the normal functioning of the gastro- 
intestinal tract is changed, the question whether such procedures have 
influenced the length of life of the given individual becomes one of 
great importance in connection with the surgical treatment of benign 
lesions of the stomach and duodenum. 

During the several years past we have been repeatedly asked by 
insurance companies whether a given patient, whom we have operated 
on for gastric or duodenal ulcer, should be accepted as a good insurance 
risk. We have had impressions as to the advisability of accepting such 
risks, but until recently we have never had any actual proof of life 
expectancy after operations have been carried out on such persons 
as compared with a group of persons in the general population of 
similar age and sex. 

* Presented before the American Surgical Association, Atlantic City, June, 1919. 
Reprinted from Ann. Surg., 1919, lxx, 5%%-5%o. 

93 



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94 D. C. BALFOUR 

As we have always realized the importance of securing positive 
information along these lines we accepted with readiness the proposal 
of the Actuarial Society of America that they should study the records 
at the Mayo Clinic and by their own methods carry out some follow- 
up investigations with regard to the length of life which maybe antici- 
pated in patients operated on for gastric and duodenal ulcer. This 
Association has recently compiled and published the statistics, and 
although, in the main, they agree with information which we have 
been able to secure for ourselves, their methods of investigation, 
their system of accurate tabulation, and, above all, their unbiased 
interpretation of such information adds unusual interest and value 
to the figures which I present. 

Unfortunately there is no basis on which the results of the present 
investigation of operated gastric and duodenal ulcers can be compared 
with the results in non-operated cases. Not only are no statistics 
available as to life expectancy in non-operated cases of gastric and 
duodenal ulcer, but accurate statistics in this group will probably 
never be entirely possible, because the uncertainties in diagnosis 
discount more or less the dependability of such figures. On the other 
hand, surgical statistics are based on proved lesions, and on lesions 
in which medical treatment has failed. If proved statistics of non- 
operative cases become available, the surgeon will welcome the 
opportunity of establishing the fact that the surgical measures of 
treatment are the most efficient from every standpoint. 

The investigation carried out by the Actuarial Society of America 
was under the direction of Mr. Arthur Hunter, Chief Actuary of the 
New York Life Insurance Company. It is first interesting to note 
the success of the methods employed by this society for tracing cases. 
Of a series of 2431 patients operated on for gastric and duodenal ulcer 
in the clinic between 1906 and 1915, all but 108 were traced, a per- 
centage record which I am sure has never before been approached. 

The figures first show that the operative mortality from all causes* 
in 545 cases of gastric ulcers in which operation was done during this 
period was 4.5 per cent, while in 1684 cases of duodenal ulcer the 
operative mortality from all causes was 2 per cent. Gastric ulcer 
carries, therefore, twice the operative risk of duodenal ulcer. 

The Association's investigations of the mortality in the years 
after operation show the following facts: 

* The cause of death has not been considered in this study . 



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GASTRIC AND DUODENAL ULCER 95 

Gastric ulcer. — Five hundred twenty-one patients were under 
observation on the average of three and six-tenth years, and in that 
time 88 (17 per cent) died from all causes. 

Duodenal ulcer. — One thousand six hundred fifty-one patients 
were under observation on the average of three and four-tenth years, 
and in that time 85 (approximately 5 per cent) died from all causes. 

Gastric and duodenal ulcer. — Ninety-one patients were under 
observation on the average of three and eight-tenth years, and in 
that time 9 (10 per cent) died. 

Mr. Hunter's first observations on these statistics are most inter- 
esting; I quote verbatim: "The fact that 17 per cent of those operated 
on for gastric ulcer have died within an average period of observation 
of three and six-tenth years, and the fact that 5 per cent of those 
operated on for duodenal ulcer have died within an average period 
of observation of three and four-tenth years, are in themselves 
significant. While we cannot tell how many lives have been saved 
by reason of operation for duodenal ulcer, it may safely be stated 
that the survival for three and a half years after the operation of 
95 per cent is a high tribute to surgery. With such a serious condition 
as gastric ulcer, a death rate in three and a half years of 17 per cent of 
those operated on appears to be low. While I cannot prove my state- 
ment, I believe that a much larger proportion of persons would have 
died but for the operation, and that many years of life in the aggregate 
were saved. through surgical treatment." 

The chief point of importance in these statistics, however, is gained 
by comparing the mortality figures of a group of patients subjected 
to operation for gastric and duodenal ulcer with a group of the general 
population corresponding in age and sex. 

Table 1. — Gastric Ulcer 

Deaths in group of 521 persons operated on 

Following Operation Deaths 

First year 36 

Second year 21 

Third year 11 

Fourth year 7 

Fifth year 7 ' 

Sixth year and subsequent 6 

88 



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96 D. C. BALFOUR 

General population group of 521 persons with like distribution as to age and sex observed 

during the same period of time 

Observation Deaths 

First year 8.2 

Second year 6.5 

Third year 4.9 

Fourth year 4.1 

Fifth year j% 3.0 

Sixth year and subsequent 5.6 

32 8 

It will be noted in Table 1 that the number of deaths in the first 
year following operation was about four and one-third times the 
deaths in a like group in the general population; in the second year this 
number was three and one-fourth times that of the general population, 
and in the later years it was still less. With an average period of 
observation, therefore, of only three and one-third years, the number 
of deaths in the year following operation, when the mortality is 
highest, has much greater weight in the total than if the observa- 
tions were conducted for a longer period. 

In duodenal ulcer a similar comparison shows most instructive 
findings. 

Table 2. — Duodenal Ulcer 

Deaths in group of 1651 persons operated on 

Following Operation Deaths 

First year 22 

Second year 20 

Third year 9 

Fourth year 10 

Fifth year 11 

Sixth year and subsequent 13 

85 

General population group of 1651 persons with like distribution as to age and sex, 

observed during the same period of time 

Observation Deaths 

First year 24 .0 

Second year 18 . 6 

Third year 14.3 

Fourth year 11.2 

Fifth year 8.3 

Sixth year and subsequent 16.7 

93.1 

Here we have the rather astounding fact that in the first two years 
following operation for duodenal ulcer the mortality is only that of the 



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GASTRIC AND DUODENAL ULCER 97 

general population group, and that after the second year the mortality- 
is actually less than in the general population group. These statistics 
illustrate very strikingly the fact which always has been recognized 
by surgeons, namely, that gastric ulcer is a much more serious con- 
dition than duodenal ulcer, not only from an operative standpoint, 
hut from a standpoint of after-results, and that the patient with a 
gastric ulcer shows, as a rule, much more evidence of impaired general 
health than the patient with duodenal ulcer. 

Summary 

1. The percentage of operative deaths in the hospital following 
operation for gastric ulcer was fully twice that following duodenal ulcer, 
but the percentage in both cases was very low considering the serious- 
ness of the condition. 

%. The mortality during the three years following the operation 
among persons operated on for gastric ulcer was three times as high 
as that among persons operated on for duodenal ulcer. 

3. The mortality among persons operated on for gastric ulcer 
decreases relatively after operation, but the data are not sufficient to 
determine the number of years which must elapse before the death 
rate is similar to that of the general population. 

4. The mortality among those operated on for duodenal ulcer in 
this series was less than that among the general population. 

5. The average age at time of operation of those operated on for 
gastric ulcer was 47 in the case of men, and 43 in the case of women; 
the average age of those operated on for duodenal ulcer was 44 and 42 
respectively. 



•19-7 



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A COMPARATIVE STUDY OF THE ANATOMY OF THE 
SPHINCTER AT THE DUODENAL END OF THE 
COMMON BILE DUCT WITH SPECIAL REFER- 
ENCE TO SPECIES OF ANIMALS WITHOUT 
A GALLBLADDER* 

F. C. MANN 



In previous investigations, 4,5 it was emphasized that the removal 
of the gallbladder was usually followed by dilatation of all the extra- 
hepatic ducts. This dilatation did not take place if all the muscle 
fibers surrounding the common bile duct in its passage through the 
duodenal wall were destroyed. Furthermore, in our experiments, the 
sphincter at the end of the common bile duct was either not physiologic- 
ally active or it was less active than in animals in which the gallbladder 
had not been removed. Because of these facts great importance is 
attached to the interrelation of the action of the gallbladder and 
sphincter. Accordingly, it was believed that an anatomic difference 
might be found between the sphincter of animals with gallbladders 
and those without them. 

This sphincter has been studied anatomically by Gage, Oddi, and 
Hendrickson. It has been said that Glisson first suspected such a 
sphincter, but Gage seems to have been the first to describe the struc- 
ture. In an extensive study of the ampulla of Vater and pancreatic 
ducts in the cat, he describes a sphincter around both the common 
bile duct and pancreatic duct, and another sphin< ter common to both 
ducts. 

Oddi made an extensive comparative investigation of the sphincter 
to which his name is usually attached. He studied the duodenal 
portion of the common bile duct by maceration and histologically in 
man, the dog, sheep, ox, pig, cat, horse, domestic pigeon, common fowl 
and guinea fowl. He found that the course of the duct through the 
duodenal wall differs in the various species of animals. The arrange- 
ment of the smooth muscle around the duct likewise differs. In each 

* Reprinted from Anat. Rec., 1920, xviii, 335-.<G0. 

98 



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ANATOMY OF THE SPHINCTER 



99 



species studied, he was able to demonstrate, however, a definite sphinc- 
ter at the duodenal end of the common bile duct. 

A most complete study of the musculation of the entire extra- 
hepatic biliary system, including that of the sphincter, was made by 
Hendrickson, in the dog and the rabbit, and in man. Both by macera- 
tion and by the microscope he was able to demonstrate a definite 
sphincter in each species. 




Fig. 41. — Photomicrograph of section of hepatic duct of pocket gopher (F. bur- 
^arius) at about the middle of the course of the duct through the muscularis of the 
duodenum. The duodenal mucosa is at the top, a lobule of pancreas at the bottom 
to the right. Note how the muscularis surrounds the duct. X40. 



According to the list of species reported by Oddi the gallbladder is 
absent in only a few, such as the horse and pigeon. In the horse the 
duct opening is quite patulous, and in the pigeon the duct system is 
complex. Since it seemed advisable to study the sphincter in other 
species without a gallbladder, we obtained specimens from four such 
species, the horse, deer, rat, and pocket gopher (G. bursarius) ;_the 
three latter had not been previously studied. As controls, we also 
studied the sphincter in the dog, cat, rabbit, guinea pig, ox, goat, pig, 
sheep, striped gopher (C. tridecemlineatus) and mouse, which possess 
a gallbladder. 



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100 



F. C. MANN 



The sphincter was studied macroscopically and microscopically; 
the latter method was found to be the more valuable because many of 
the specimens were very small. The specimen of the sphincter was 
secured immediately after the death of the animal and placed in the 
fixative, usually formalin. The specimen was subsequently trimmed 
to the smallest size that would give the complete course of the duct, 
and paraffin serial sections were made. 




Fio. 42. — Photomicrograph showing a higher magnification of the same section 
shown in Figure 41. Not only does the m'uscularis surround the duct but there are a 
few fibers seemingly passed around the duct and interlacing with the muscle fibers of 
the muscularis. X100. 

This study corroborates the observations of previous investigators 
with regard to the variability of the course of the duct through the 
duodenal wall in the various species of animals. In each species the 
course seems to differ slightly from that of other species. This 
difference seems to depend mainly on the direction of the duct in 
relation to the axis of the duodenum and the thickness of the duodenal 
walls. The relation of the course of the duct to the course of the 
duodenum was difficult to determine. Angles of various degrees 
between the course of the duct and the direction of the long axis of 
the duodenum are noted in various species. In some species the two 



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ANATOMY OF THE SPHINCTER 



101 



are almost parallel for a relatively long distance, but the duct gradually 
passes through the duodenal wall. In other species the duct seems 
to pierce the wall of the intestine almost at right angles, but of course 
it does not actually do so. In a few species the duct turns almost 
at a right angle to the direction of its course within the duodenal wall. 
The relative position of the duct to the duodenal wall seems to depend, 
in a great measure, on the latter. In some species the intramural 




Flo. 43. — Photomicrograph of section of hepatic duct of a rat, taken at the point 
where the duct passes into the sub mucosa of the duodenum. The duodedal mucosa 
is at the top, a lobule of pancreas below the muscularis to the left. X40. 



portion of the duct is relatively short, particularly in some of the 
species in which the intestinal wall is thin. In other species the intra- 
mural portion of the duct is relatively long. This is due either to a 
prolongation of the portion of the duct in the muscle- wall, or, as is 
usually the case, to the extension of the duct in the submucosa for some 
distance. The opening of the duct through the mucosa also differs 
in the various species; in most it is no larger than a pen point, but in 
a few it is patulous. It should be noted that both the direction of 
the duct through the duodenal wall and the method of opening into 
the duodenum do not differ in species of animals without a gallbladder, 
as a group, from species of animals possessing a gallbladder. 



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102 



F. C. MANN 



The bile duct in each species was found to be surrounded by a 
bundle of smooth muscle, contraction of which closes the lumen of 
the duct. The amount of muscle-tissue and the arrangement of it 
differs considerably in the various species, depending probably on the 
difference in the thickness of the wall of the duodenum and the course 
of the duct. In many species it is rather difficult to find muscle 
fibers which encompass the duct exclusively, because they are so closely 



« :<v ■]£#' 













Fig. 44. — Photomicrograph of higher magnification of same section shown in 
Figure 43. There is a relatively large bundle of muscle which completely surrounds 
the duct and interlaces with the muscularis of the duodenum. The sphincter is com- 
parably as well developed in the rat as any species studied. XI 00. 

intermingled with the circular fibers of the intestine. As a matter 
of fact in many specimens the muscle fibers which might act exclusively 
as a sphincter are very few. Sometimes there is only an accentuation 
of the muscle coat in the intramural portion of the duct which has 
extended from the extramural portion. When the arrangement of 
the circular muscle fibers of the intestine is considered in connection 
with the fibers which undoubtedly surround the duct, it is justifiable 
to conclude that a definite sphincter exists in each species studied. 

No constant difference was observed in the histology of the sphinc- 
ter in animals with a gallbladder as compared to those without one, and 



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ANATOMY OF THE SPHINCTER 103 

no specific anatomic difference was found between the sphincters in 
the two groups of animals. 

Summary 

An anatomic study was made of the sphincter of the duodenal end 
of the common bile duct in ten species of animals with gallbladders 
and four species without. Considerable difference was found with 
regard to the course of the duct through the duodenal wall, and in the 
arrangement of the muscle fibers around the duct. There is a definite 
arrangement of muscle fibers which might functionate as a sphincter 
in each species studied; no difference could be observed in animals 
that have a gallbladder when compared with those without one. 
There is no doubt that anatomically some species of animals lacking 
a gallbladder have an arrangement of muscle around the duodenal 
end of the bile duct which can act as a sphincter. 

BIBLIOGRAPHY 

1. Gage, S. H.: The ampulla of Vater and the pancreatic ducts in the domestic 
cat (Felis domestica). Am. Quart. Micr. Jour., 1879, i, 128; 169. 

2. Glisson: Quoted by Oddi. 

3. Hendrickson, W. F.: A study of the musculature of the entire extrahepatic 
biliary system, including that of the duodenal portion of the common bile duct and of 
the sphincter. Bull., Johns Hopkins Hosp. 1898, ix, 221-232. 

4. Judd, E. S., and Mann, F. C: The effect of removal of the gall-bladder. An 
experimental study. Surg., Gynec. antf Obst., 1917, xxiv, 437-442. 

5. Mann, F. C: The function of the gall-bladder. An experimental study. New 
Orleans Med. and Surg. Jour., 1918, lxxi, 80-92. 

6. Oddi, R.: D'une disposition a sphincter spcciale de Touverture du canal chole"- 
doque. Arch. ital. de biol., 1887, viii, 317-322. 



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A STUDY OF THE TONICITY OF THE SPHINCTER 
AT THE DUODENAL END OF THE COMMON 

BILE DUCT* 

With Special Reference to Animals without a Gallbladder 

f. c. MANN 



Previous work on the function of the gallbladder has shown that 
cholecystectomy is usually followed by dilatation of all the extrahe- 
patic ducts. This dilatation is dependent on an intact sphincter at 
the end of the common bile duct. This would seem to imply that 
there is some relation between the action of the sphincter and that 
of the gallbladder, a possibility which has been used by Oddi and 
M eltzer in explaining the cause of some of the diseases of the biliary 
tract. In a study of the anatomy of the sphincter, no difference was 
found in species of animals with a gallbladder as compared with those 
without one. 3 A comparable study of its physiology was therefore 
made. 

The physiologic action of the sphincter at the duodenal end of 
the common bile duct has been studied, although only in the dog 
and the cat, by Oddi, Archibald, and Rost; only the two former in- 
vestigators measured the tone of the sphincter. Oddi found that the 
sphincter in the dog withstood a pressure of about 50 mm. of mercury 
or an equivalent of 675 mm. of water. Archibald found that the 
sphincter in this same species withstood a pressure as high as 600 mm. 
of water. Both investigators found that mechanical or chemical 
irritation throws the sphincter into a spasm. 

A series of observations on the physiologic action of the sphincter 
has been made in our laboratory; a complete report will be made 
later. The present article deals only with a comparison of the tone 
of the sphincter in species with a gallbladder and in those without 
one. We had access for this research to only two species in which 

* Reprinted from Jour. Lab. and Clin. Med., 1919, v, 107-110. 
104 



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TONICITY OF THE SPHINCTER 105 

the gallbladder was lacking, the rat and pocket gopher (G. bursarius).* 
For controls the dog, cat, goat, rabbit, striped gopher (C. tridecem- 
Hneatus), and guinea pig were used. 

The method of estimating the tone of the sphincter was simple. 
The animal was lightly etherized; in a few experiments urethan was 
used, a cannula was carefully placed in the common bile duct (in 
the species without a gallbladder in the hepatic duct), as far as practi- 
cable from the duodenum, with its point directed toward the duodenum. 
A T-tube was attached to the cannula and one arm of the tube was 
arranged so that it could be connected to a syringe; the other arm was 
connected to a straight glass tube. This T-tube was about 50 cm. in 
length and had an internal bore of approximately £.5 cm. The glass 
tube was graduated in millimeters. Great care was taken to keep 
the duodenum protected during the operative procedures. 

The tone of the sphincter was estimated by two methods: First, 
an aqueous eosin solution was passed slowly arid cautiously into the 
tube until the point at which it began to flow into the intestine was 
reached. The findings were recorded. Second, the solution was 
passed quickly into the tube to a high pressure and the point noted 
at which it ceased to flow into the intestine. In both instances the 
length of the column of water, after the fluid became stationary, was 
taken as a measure, expressed in millimeters, of the tone of the sphinc- 
ter. The specific gravity of the eosin solution was but slightly greater 
than that of distilled water and, since the study was a comparative 
one, this difference was ignored. The solution was either at body or 
room temperature. Care was taken to have the system free from air 
before beginning observations. It is obvious that this method does 
not give absolutely the correct measure of the tone of the sphincter 
as there are many complicating factors and sources of error. The 
major portion of the errors may be attributed to two causes: First, 
the pressure taken as the measure of the duct might be due to other 
factors, such as friction, and so forth, making the reading greater than it 
should be. Second, the anesthetic and operative manipulation might 
decrease the muscle tone, tending to make the measured pressure less 
than the pressure of the duct really was. As a matter of fact both 
of these factors were found to be sources of error, but they were in 
the main obviated so that an approximate reading could be made. 

* These experiments were completed in 1917, but publication was delayed because 
of attempts to obtain data from a larger number of species lacking a gallbladder. The 
pigeon and horse were used, but technical difficulties caused failure. 



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106 F. C. MANN 

The amount that the reading was complicated by resistance to outflow 
other than that produced by the tone of the sphincter was deter- 
mined by taking another reading after deep etherization, bleeding* 
and formalin injections into the duct and after the death of the animal. 
It was thus determined that the residual pressure was practically a 
measure of the tone of the sphincter in large ducts, as in the dog and 
goat; in the smaller animals, a correction of 10 per cent might occasion- 
ally have to be made. The part the anesthetic played in complicating 
the experiment was studied by using ether, urethan, and, in the case 
of the dog, the development of a method of studying the action of the 
sphincter in an unanesthetized animal. From the results of the control 
methods it seemed that the anesthetic as administered did not offer 
a very great source of error. The operative manipulations also pro- 
duced changes, either an increase or a decrease in the tone of the 
sphincter. Peristalsis was also considered, because peristaltic waves 
affect the outflow frorti the common bile duct. 

The pressure which seemed to measure the tone of the sphincter 
was found to vary considerably in the different species and different 
individual animals. However, the sphincter in each species of animal 
possessing a gallbladder, except the guinea pig, withstood a minimum 
pressure of 100 mm. water; sometimes the pressure was much greater, 
very rarely it was less. In the guinea pig, the pressure withstood 
was rarely more than 75 mm. and frequently considerably lower; this 
seemed to be due to the fact that as the common bile duct is very short 
in this species, the trauma incident to the insertion of the cannula 
was great. In a very few animals of other species the sphincter did 
not seem to have any tone. 

The pocket gopher and rat were the only suitable species without 
a gallbladder obtainable for investigation of the tone of the sphincter. 
The results of a large number of experiments are the same; in no 
instance was any pressure, or at the most only a very slight pressure, 
usually not more than 30 mm., maintained by the sphincter. In 
most cases, all the fluid passed into the duodenum, leaving only a 
very slight residual pressure. 

As I have stated, it was very difficult because of many complicating 
errors to evaluate the results in this investigation. In the dog and 
cat, which had been studied by previous investigators, our results did 
not show that the sphincter withstood so great a pressure as that 
recorded by others. On the other hand, some evidence of a sphincteric 



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TONICITY OF THE SPHINCTER 107 

tone was found in each species with a gallbladder. Even in the guinea 
pig there was definite evidence of this action. No such evidence was 
obtained in the two animals lacking a gallbladder, the rat and the 
pocket gopher, although many experiments were performed. When 
the mass of data from a large series of experiments is considered, this 
distinction between the two groups of species becomes very clear. 

Summary * 

The tone of the sphincter at the duodenal end of the common bile 
duct was studied in species of animals possessing a gallbladder and in 
two species in which the gallbladder is lacking. It was found that the 
tone of the sphincter under the experimental conditions studied varied 
considerably in the different animals and various species. In each 
species possessing a gallbladder, however, the sphincter was usually 
able to withstand a minimum pressure of from 75 to 100 mm. water. 
In the species lacking a gallbladder, the sphincter would not withstand 
pressure, or only pressures of less than 30 mm. water. While anatomic 
studies have shown that a sphincter is present in each species lacking 
a gallbladder, the sphincter does not seem to functionate appreciably. 

BIBLIOGRAPHY 

1. Archibald, E.: Does cholecystenterostomy divert the flow of bile from the com- 
mon duct? Canad. Med. Assn. Jour., 1912, ii, 557-562. The experimental production 
of pancreatitis in animals as the result of the resistance of the common duct sphincter. 
Surg., Gynec. and Obst., 1919, xxviii, 529-545. 

2. Judd, £. S., and Mann, F. C: The effect of removal of the gall-bladder. An 
experimental study. Surg., Gynec. and Obst., 1917, xxiv, 437-442. 

S. Mann, F. C. : A comparative study of the anatomy of the sphincter at the duo- 
denal end of the common bile duct with special reference to species of animals without 
a gallbladder. (In manuscript.) 

4. Meltzer, S. J.: The disturbance of the law of contrary innervation as a pathoge- 
netic factor in the diseases of the bile ducts and the gall-bladder. Am. Jour. Med. Sc. 
1917, cliii, 469-477. 

5. Oddi, R.: D'une disposition a sphincter speciale de l'puverture du canal chole- 
doque. Arch. ital. de biol., 1887, viii, 317-322. Sulla tonicita dello sfintere del cole- 
doco. Arch, per le sc. med., 1888, xii, 333-339. 

6. Host, F.: Die funktionelle Bedeutung der Gallenblase. Experimen telle und 
anatomische Untersuchungen nach Cholecystektomie. Mitteil. a.d. Grenzgeb. d. Med. 
u. Chh\, 1913, xxvi, 710-770. 



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EARLY LESIONS IN THE GALLBLADDER* 

W. C. MACCARTY AND J. R. CORKERY 

The study of early pathologic conditions in the gallbladder has 
been greatly facilitated by cholecystectomy, an operation which many 
surgeons have deemed advisable in preference to cholecystostomy. 
In their experience, many patients in whom the organ had been drained 
returned to them with symptoms unrelieved. The desired relief in 
such cases seems to have been accomplished, at least in a much higher 




Fig. 45. — Villi of a gallbladder in an early stage of congestion and edema. 

percentage, by the secondary complete removal of the organ. This 

experience with such cases following a secondary cholecystectomy has 

led, in the last five years, to the custom of primary cholecystectomy in 

preference to cholecystostomy in patients with a visible lesion and also 

in some patients in whom there is no visible gross pathology but a 

* Presented before the American Gastro-Enterological Association, Atlantic City, 
June, 1919. 

Reprinted from Am. Jour. Med. Sc., 1920, clix, 646-853. Copyright 1920, by 
Lea and Febiger. 

108 



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EARLY LESIONS IN THE GALLBLADDER 109 

definite clinical picture pointing to this organ, plus enlargement 
of lymphatic glands along the ducts. 

From Jan. 1, 1913 to Jan. 1, 1919, 4,998 gallbladders were removed 
at the Mayo Clinic. Of these, 4,824 (96.5 per cent) showed unques- 
tioned gross pathologic lesions (Table 1). 

In this series of conditions it may be seen that there were 157 
with slight lesions and 17 grossly "normal," most of which showed 
definite changes in the villi on examination with a high power dissec- 
ting microscope or in microscopic sections. 

Table 1. — Classification of 4,998 Gallbladders 

Specimens 

1. Cholecystitis catarrhalis aeuta 17 

Cholecystitis catarrhalis acuta (with "strawberry" appearance) 9 

2. Cholecystitis catarrhalis subacuta 1 12 

Cholecystitis catarrhalis chronica 2,021 

3. Cholecystitis catarrhalis chronica (with "strawberry" appearance) 948 

Cholecystitis catarrhalis chronica (with adenoma in the wall) 1 

Cholecystitis catarrhalis chronica (with accessory fundus) 1 

Cholecystitis catarrhalis chronica (with diverticula) 4 

Cholecystitis catarrhalis chronica (with old perforation) 1 

Cholecystitis catarrhalis chronica (with very slight lesion) 38 

Cholecystitis catarrhalis chronica (?) 157 (3.1 per cent) 

4. Cholecystitis catarrhalis papillomatosa. 212 

Cholecystitis catarrhalis papillomatosa (with "strawberry" appearance). 129 
Cholecystitis catarrhalis papillomatosa (with "strawberry" and cystic 

appearance) 1 

Cholecystitis catarrhalis papillomatosa (with a diverticulum) 1 

Cholecystitis catarrhalis papillomatosa (subacuta) 1 

Cholecystitis catarrhalis papillomatosa (malignum ) 1 

Cholecystitis catarrhalis papillomatosa (malignum (?)) 1 

5. Cholecystitis catarrhalis (carcinomatosa) 22 

Cholecystitis catarrhalis carcinomatosa (?) 1 

6. Cholecystitis chronica 900 

Cholecystitis chronica (with honeycomb appearance) 8 

Cholecystitis chronica (with perforation of wall) 1 

Cholecystitis chronica (with calcification of wall) 1 

7. Cholecystitis chronica cystica 112 

r Cholecystitis chronica cystica (empyema) 24 

8. Cholecystitis acuta 81 

Cholecystitis acuta (with perforation of wall) 1 

9. Cholecystitis purulenta necrotica ' 168 

Cholecystitis purulenta necrotica (with "strawberry" appearance) 5 

10. Cholecystitis ulcerosa 1 

11. Cholecystitis epitheliomatosa (with gall stones) 1 

12. "Normal" gallbladders (gross diagnosis) 17 (0.34 per cent) 



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110 



\V. C. MacCARTY AND J. R. CORKERY 




Fig. 46. — Villi of a gallbladder showing congestion and distortion in early 

cholecystitis. 




Fig. 47. — Edematous villi having a bulbous appearance and showing pale areas- 
which are due to deposits of a lipoid substance in the epithelium or just beneath the 
epithelium in the connective tissue stroma. 




Fkj. 48. — Villi in an edematous condition. 



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EARLY LESIONS IN THE GALLBLADDER 



111 






Fig. 49. — A condition of edema of the villi associated with deposits of lipoid material 
in the epithelium and stroma. 







WEHB 

wfmm 




mi®;?' 



mm 

gofers*-. ., • 



mm 



Fig. 50. — Diagrammatic sketch 
showing the location of lipoid 
substance in the epithelium. 
Made from a section stained 
with scarlet R. 



Fig. 51. — Diagrammatic sketch 
showing the location of the lipoid 
substance in the cells but near the 
stroma. 










Fio. 52. — Diagrammatic sketch showing the lipoid substance in the epithelium and 

in the cells of the stroma. 



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112 



W. C. MacCARTY AND J. R. CORKERY 



The early changes in the gallbladder consist of: 

1. Congestion and edema of the villi frequently associated with a 
bulbous appearance (Figs. 45, 46, 47, and 48), which, on casual gross 
examination make the villi appear cystic. Occasionally they are cystic. 





&?A 




d) 


JWL'f 


& 


vA 






jr'.^j 


{f.A 


WSu s\ 








j_ j i ?yf.,' 










"JHHi 



Fig. 53. — Section through the mucosa of a gallbladder in a mild condition of chronic 
catarrhal cholecystitis. The villi contain many lymphocytes. 

The mucosa in advanced stages of this congestion and edema sometimes 
presents the appearance of being covered with small fish scales (Fig. 
49), an appearance which is due to the presence of a lipoid infiltration 
in the stroma or epithelial cells (Figs. 50, 51, and 52). 




Fio. 54. — Section through the mucosa of a gallbladder showing lymphocytic infiltra- 
tion of the villi and the underlying stroma. 

2. Local or general slight degree of lymphocytic infiltration which 
manifests itself only in a slight enlargement of the villi (Figs. 53 and 54) 
and a cloudy or duller appearance. 

3. Local or general slight degree of lymphocytic infiltration is 



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EARLY LESIONS IN THE GALLBLADDER 



113 



seen in the mucosa alone, which might possibly be considered normal 
since the mucosa probably contains a certain number of lymphocytes 







Fig. 55. — Section of the submucosa of a gallbladder, showing lymphocytic infiltration 

and fibrosis. 

but when seen in association with a lymphocytic infiltration in the sub- 
mucosa, muscularis, and subserosa(Fig. 55) very probably indicates a 




Fig. 56. — Section through the mucosa of a gallbladder showing lymphocytic 
infiltration and fibrosis in the villi. There is a glandular increase and the villi have lost 
their tentacular "appearance. 

pathologic condition. Such infiltration is associated with a bulbous 
appearance of the villi or a thickening of the bases of the villi (Figs. 
Wand 57). 

*19-S 



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114 



W. C. MacCARTY AND J. R. CORKERY 



4. The presence of fibrosis (Fig. 57) in the villi which usually are 
not thin and tentacular (in sections) like those of the perfectly normal 
organ. The fibrosis sometimes extends into the submucosa, muscularis, 
and subserosa (Fig. 55). 

5. The presence of lymphocytic infiltration and fibrosis, such as 
described above, plus the presence of a finely granular or lipoid 
substance in the epithelium (Figs. 50 and 51) or just below the epithe- 
lium in the mucosa (Fig. 52). 

6. The presence of slight or no lymphocytic infiltration and fibrosis 
plus the presence of large spheroidal cells filled with finely granular 
lipoid substance in the mucosa and sometimes in the submucosa (Fig. 




Fig. 57.- 



-Section through the mucosa of a gallbladder showing lymphocytic infiltra- 
tion, fibrosis, and distortion of the villi. 



52). Thqse cells are similar to those which have been described in the 
so-called "strawberry" gallbladder 2,3 and in papillomas. 1 This sub- 
stance may not be visible grossly but may sometimes be detected 
with the high power dissecting microscope (Fig. 47). It is the sub- 
stance which gives villi in the "strawberry" gallbladder and papillo- 
mas their yellow or white appearance. 

The conditions which have been described above do not alter the 
gross exterior of the organ, nor do they alter greatly the internal 
appearance to the naked eye. 

It is this group of slight pathologic reactions which has made many 



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EARLY LESIONS IN THE GALLBLADDER 115 

surgeons, who believe that a cholecystectomy is the operation of 
choice in cholecystitis, somewhat slow in carrying out their belief 
in practice. Also, it is probably this group which is so frequently seen 
in association with stones and has led many observers to believe that 
stones occur in perfectly normal gallbladders. 

With our present knowledge we are not prepared to say definitely 
that such early conditions alone present sufficient symptoms to make 
a definite clinical syndrome, especially in view of the fact that recent 
studies made by one of us (MacCarty) indicate that such conditions 
in the gallbladder are also associated with somewhat similar changes in 
the extrahepatic and intrahepatic bile ducts, which might readily 
interfere with hepatic function and, therefore, produce clinical dis- 
turbances. As a matter of fact, such patients do present some gen- 
eral disturbances which clinicians refer to under the broad heading of 
toxemia. 

This paper has for its object the stimulation of greater interest and 
more detailed research in conditions of the bile passages which have 
heretofore been mistaken for normal. 

BIBLIOGRAPHY 

1. Irwin, H. C. and MacCarty, W. C. : Papilloma of the gall-bladder. Report of 
85 cases. Ann. Surg., 1915, Ixi, 725-720. 

2. MacCarty, W. C. : The pathology of the gall-bladder and some associated lesions. 
A study of specimens from S65 cholecystectomies. Ann. Surg., 1910, li, 651-669. 

3. MacCarty, W. C: The frequency of "strawberry" gallbladder. Ann. Surg., 
1919, brix, 131-134. 



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JAUNDICE AND ITS SURGICAL SIGNIFICANCE* 

C. H. MAYO 

Jaundice as a symptom of disease may present a very serious prob- 
lem in tracing its cause. In approximately 50 per cent of the cases 
seen the absorption of the bile is due to obstruction of the common 
duct by gallstone; in 20 per cent of all cases it is due to absorption 
of bile in the liver, or infective or catarrhal jaundice without duct 
obstruction. Most of the latter cases occur in children and young 
persons, just enough occurring in middle age and later to make a diff- 
erential diagnosis necessary, as attacks of pain sometimes accompany 
this infectious disease or the patients actually have gallbladder disease. 

It is not my intention to discuss the diagnosis of the various causes 
of jaundice, but to consider the treatment of obstructive jaundice in 
cases in which the patient is on the table, the abdomen is open, and 
jaundice is either present, or the patient is having a free interval be- 
tween recurring attacks. The surgeon must have in mind the fact that 
jaundice is an essential feature of several conditions, and that it is an 
indication of serious disease in the majority of cases. The idea that 
jaundice may be a symptom in fairly normal persons over long periods 
evidently came about from the observation of hemolytic acholuric 
jaundice caused by splenomegaly, a surgically curable disease, some- 
times complicated with gallbladder disease and stones. From 5 to 8 
per cent of cases of jaundice are due to serious infection of the gall- 
bladder, possibly gangrene, with or without stones; they are usually 
accompanied by a degree of pancreatitis with marked swelling of the 
lymph glands on the three ducts; all persons have one on each duct 
but no one more than two. The liver is congested and dark; the ducts 
are slightly enlarged and contain much flocculent material which is 
also found in the gallbladder in which stones are usually present. 

Jaundice from cancer presents a very serious problem, although it 
represents but 15 per cent of the cases seen; one-half of these are 
from cancer of the liver, the other half from cancer of the pancreas, 

* Presented before the Western Surgical Society, Kansas City, Mo., December, 
1919. 

Reprinted from Surg., Gynec., and Obst., 1920, xxx, 545-549. 

116 



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JAUNDICE AND ITS SURGICAL SIGNIFICANCE 117 

or the gallbladder and ducts. Patients with cancer of the pancreas 
or in the ampulla of Vater may be relieved, often for many months 
by short-circuiting the obstructed area. We have not had a perma- 
nent cure from transduodenal extirpation of tumor of the ampulla; 
and it must be admitted also that it is sometimes difficult positively 
to determine whether the hardening of the pancreas causing obstruc- 
tive jaundice is of a malignant or of an inflammatory nature. Jaun- 
dice from cirrhosis, with ascites usually present, occurs in about 8 
per cent of cases. The old classification made by Courvoisier still 
remains a true observation, in which in about 84 per cent of the cases 
of stone in the common duct the gallbladder was shrunken or atrophied 
while in 92 of 100 cases of obstruction due to lesions in the ampulla or 
pancreas or other conditions, the gallbladder was dilated or enlarged; 
in the remaining 8 cases it was either normal or atrophic. 

In cases of chronic jaundice with obstruction the distended gall- 
bladder and ducts are often filled with a clear mucoid fluid indicating, 
I believe, that the power of the mucous gland to secrete the less ab- 
sorbable mucus which fills the ducts is greater than the power of the 
liver to secrete bile, and forces the liver with its lower blood pressure 
to absorb the bile. In cases of late operation at which the so-called 
white bile is found, failure of the power of biliary excretion to appear 
within a day or two following the operative drainage is a most unfav- 
orable symptom. Long continued jaundice slows the coagulation time 
of blood; as a rule if the coagulation time is under ten minutes it is 
not of serious moment, but a ten to twenty-five minute period is not 
uncommon, and in some cases the blood will not coagulate in an hour. 
Patients in whom the blood leaves the vessels as shown by numerous 
subcutaneous hemorrhages should be medical cases until improvement 
occurs before surgery is indicated. Calcium has been given, with 
questionable relief, to reduce the delayed coagulation time of patients 
with chronic jaundice who are being prepared for operation. The 
best measure in cases with twelve minutes or more coagulation time 
is the transfusion of acceptable human blood. Patients whose coagu- 
lation time is greatly reduced are given one transfusion and the blood 
is tested the next day. If improvement is marked operation is per- 
formed, but if improvement is slight transfusion is repeated just pre- 
ceding the operation, and, if there is hemorrhage during the next few 
days, transfusion is again repeated with occasional benefit. 

If the gallbladder shows marked evidence of disease, especially 



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118 C. H. MAYO 

in cases of stone in the common duct, a cholecystectomy is performed 
After removal of the gallbladder the cystic duct is split through into 
the common duct to permit of an exploration; here the pliable metal 
spoons and bulb-tipped probes and the Gusse fenestrated stone for- 
ceps of Various sizes are useful. In the rare instances in which the 
gallbladder has already been removed a more favorable location than 
the cystic duct area can be selected. In more severe infection with 
degrees of gangrene the gallbladder should be removed unless the serious 
condition of the patient makes haste imperative; then it is drained 
with or without drainage of the common duct, depending on whether 
or not bile flows from the gallbladder. 

In such cases the gallbladder is split on each side with scissors 
from top to bottom one quarter of an inch from its attachment to 
the liver. The free flap is turned downward, exposing the obstructing 
stone in the cystic duct; the duct is clamped in forceps and divided. 
The mucous membrane remaining on the liver attachment readily 
peels off, leaving the outer layer of the gallbladder for protection 
since if this should be peeled off serious hemorrhages, difficult to 
control may result. Suturing such a liver adds to the infective condi- 
tion for the liver structure does not permit of drawing sutures suffi- 
ciently tight to check serious hemorrhage from its surface; this is one 
of the reasons why cholecystostomy has been made in some cases. A 
knowledge of the size <of the various ducts is quite essential; in a 
healthy person the lumen of the cystic'duct is about one-eighth of an 
inch and the lumen of the common duct about one-sixth of an inch. 
When it is only a little enlarged and with jaundice present infection 
is the essential factor. A gallbladder which has been rendered function- 
less by nature, disease, or operation causes dilatation above the normal 
of the common and hepatic ducts. A serious and not uncommon cause 
of jaundice is the too radical extirpation of the gallbladder and cystic 
duct and section of the common duct in cases in which jaundice was 
not a previous symptom, and in which the hepatic duct is mistakenly 
ligated for the cystic; primary jaundice and later a prolonged biliary 
fistula result, following which intermittent closure leads to intermittent 
jaundice. In such cases if the condition is not recognized immediately 
-and very early union effected by means of a Sullivan T-tube the com- 
mon duct undergoes atrophy and cannot be utilized again. The 
effort to secure delivery of bile from direct incision of the liver or by 
trocar, tapping a dilated duct, is a last resort from which relief is only. 



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JAUNDICE AND ITS SURGICAL SIGNIFICANCE 119 

temporary, and if unsuccessful life is possibly shortened by free 
hemorrhage. 

Jaundice in which the head of the pancreas shows marked hardness, 
lobulation, and increase in size, requires most careful consideration. 
If the gallbladder is distended the condition is due either to pancrea- 
titis or to a malignant change, since the pancreas, as Opie has shown 
surrounds the common duct in 32 per cent of persons sufficiently to 
make obstruction possible by pressure. Obstruction from swelling 
at the tip of the ampulla may cause a pancreatitis by forcing bile 
through the major duct of Wirsung back into the pancreas and out 
of the duct of Santorini. The pancreas, in its development, is evi- 
dently prepared for such emergencies since all the ducts of the organ 
open into the lumen of the larger ducts by passing along its wall for 
some distance. The closure of the ducts is caused by tension, which 
is nature's method of protecting all important ducts, such as the 
salivary and common ducts, and the ureters near their exits, as was 
shown by Coffey. 

A careful examination of the pancreas in all cases of gallbladder 
disease or surgical gastric disease indicates that the pancreas is secon- 
darily involved by infection following gallbladder disease more fre- 
quently than has been supposed. When secondary infection of the 
pancreas is a marked feature of gallbladder disease it may be advisable 
to provide drainage from the common duct, but usually the gallbladder 
may be looked on as a primary focus, and should be removed. In 
most of the simple obstructions due to stones in the common duct 
effective drainage is established after removal of the stones by means 
of the Robson tube passed into the opening of the common duct and 
up into the hepatic duct. The tube is held by a fine catgut suture as 
it emerges through the common duct incision. The suture serves also 
to close the opening about the drain. In cases of obstruction asso- 
ciated with distention of the gallbladder short-circuiting is best done 
by attaching the gallbladder, after it has been emptied, to the duo- 
denum. An opening one-half inch in diameter is made in the fundus 
of the gallbladder, the peritoneum is denuded for about one-quarter 
of an inch from the opening; it is then passed for one-quarter of an 
inch, through an incision at a conveniently near point, into the lumen 
of the duodenum. Such openings prove more permanent than the 
margin-to-margin union of the opening in the gallbladder to the open- 
ing in the duodenum. In some cases with elongated cystic duct the 



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120 



C. H. MAYO 



gallbladder is removed down to its pelvis and this is passed through 
an opening in the duodenum which is then sutured around the cystic 
duct (Fig. 58). 

Probably the most desperate and difficult cases of jaundice to deal 
with are those which follow extirpation of the gallbladder and uninten- 
tional division of the common duct. The distended hepatic duct is 
searched for, usually among the adhesions of from two to four previous 




Fig. 58. — (a) Sullivan tube for common duct drain; (6) buried tube (C. H. Mayo) for 
uniting hepatic duct to stomach or duodenum. 

operations, or the temporary discharging fistula leading to the hepatic 
duct is followed. In cases in which the end of the hepatic duct is 
found opposite the duodenum or opposite the pyloric ring the pylorus 
and duodenum are also mobilized and the union is made to the duo- 
denum ; this is the preferable method. Often the prepyloric region 
of the stomach is found adherent beside the opening of the duct. In 
such cases it is best to disturb the adhesions as little as possible and 



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JAUNDICE AND ITS SURGICAL SIGNIFICANCE 



121 



to anastomose the hepatic duct to the prepyloric portion of the stomach. 
To maintain this opening until nature contracts the tissues, developing 
firm union and a mucous-lined tube, it is only necessary to unite the 
end of the duct to the mucosa of the stomach or bowel (Fig. 59). 

To facilitate this I have devised a drain which has proved most 
efficient and is made by cutting off the bell end of an ordinary male 
catheter, slipping two small rings cut from the next larger sized cathe- 



x - hi 



Soa,* a/fc svte of gatLL blaLcLdec 

Chromic 
ca/tgu-t or- 




Hepa,£vc duct A>$^ v - >k 

Duoden.a.1 ttiu-cossl 



Fiq. 59. — Preparation for anastomosis of hepatic duct and duodenum. 

ter over the smaller part of the tube, and gluing these rings with rubber 
cement. This little drain, varying in length from one and one-half 
to two and one-fourth inches, is passed bell end upward into the hepa- 
tic duct, which has been loosened for a short distance. The catheter 
drain is sutured to the end of the hepatic duct and an opening is made 
into the bowel or stomach through which the lower end of the drain is 
passed, the lower ring catching in the wall of the bowel or stomach and 
the second ring just inside the end of the hepatic duct; the outer wall 



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122 



C. H. MAYO 



of the stomach or bowel is sutured around the end of the hepatic duct 
and protected by gastrohepatic or gastrocolic omentum adjusted 
around the anastomosis by sutures. The rings on the tube may hold 
it in place for as long as several months, or until the contraction has 
relaxed and the mucous membrane of the duct is united to the lumen 
of the bowel or stomach. In cases in which this union to the stomach 
is made all the bile passes into the stomach, but this is of no serious 
consequence and does not give any distressing symptoms (Fig. 60). 

3ca.v at 31/fce of 
gall-Ua.bLaer \) 




Inter cu.pt ed, 

sutu/ces Ln, 

Kepa/fcLc du-ot xX <|j^^ 

axveL serou.3 jla»p 

oy dLu-ocLen-TJLTn, \ 

. 

Fig. 60. — Suturing partially completed; tube in place. 

During the years 1916, 1917, and 1918 in 13 cases seen it was neces- 
sary to unite. the hepatic duct either to the duodenum or to the stomach; 
two of the patients died. Jaundice is a late symptom of gallstone, in 
the majority of cases the result of neglect to recognize the condition 
or to advise operation in the preventive period. The mortality 
following cholecystectomy in the treatment of cholecystitis with or 
without stones is low, only 1.8 per cent in 2,460 operations performed 
during the period of three years. There were 337 cases in which 



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JAUNDICE AND ITS SURGICAL SIGNIFICANCE 123 

cholecystectomy and choledochotomy were both done, with a mortality 
of 3.2 per cent. In a group of 36 cases of very serious obstruction and 
malignancy cholecystostomy and choledochotomy were done with a 
mortality of 16.6 per cent. Choledochotomy alone was done in a 
somewhat similar group of 47 cases, with a mortality of 15 per cent. 
If all the choledochotomies are grouped together, however, the mor- 
tality in the 420 cases is but 5.7 per cent, too high a mortality for 
simple cases of stone and obstruction, and too low for the late and 
complicated cases, including the cancers. Stones were found in the 
common duct in 274 of the 420 cases. 



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THE HISTOGENESIS OF CARCINOMA IN THE ISLETS 
OF THE PANCREAS* 

E. J. HORGAN 



The earliest stages of carcinoma have been found in association 
with chronic inflammatory changes in many organs of the body; 
therefore it seemed theoretically possible that similar neoplastic 
changes might be found in association with chronic pancreatitis. 
With this idea in mind I examined 262 pancreases which were removed 
at necropsy from patients who died with ulcer of the stomach, ulcer 
of the duodenum, cholecystitis with and without stones, cholangitis 
with and without stones, and carcinoma of the stomach, liver, gallblad- 
der, and bile ducts. In no case in this series was a definite advanced 
carcinoma of the pancreas studied, although comparison was made of 
thirty-six specimens of tissue from late carcinoma with the tissue 
showing early changes. 

In the cases available for study the pathologic conditions of the 
pancreas found in association with those chronic upper abdominal 
lesions mentioned were acute and chronic pancreatitis, stages of fat 
necrosis, simple cysts, cyst adenomas, papillary cystadenomas, hyper- 
trophy and hyperplasia in the islets of Langerhans. Of these condi- 
tions, hypertrophy and hyperplasia in the islets in chronic pancreatitis 
were selected as the object of this special investigation. In order to 
obtain more accurate knowledge which might throw light on the 
histogenesis of carcinoma of the pancreas, a detailed study of patho- 
logic specimens, grossly and microscopically, was made. This was 
supplemented by the study of the normal development and structure 
of the pancreas. 

Embryology 

The pancreas in man develops from two anlages which appear 

in the embryo of 3 to 4 mm. in length. The dorsal pancreatic 

anlage begins as an outpouching on the duodenum, the ventral 

pancreatic anlage as a grooved bud arising from the common bile 

* Reprinted from Jour. Lab. and Clin. Med., 19S0, v, 420-442. 
124 



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THE HISTOGENESIS OF CARCINOMA 



125 



duct (Fig. 61). The growth of the dorsal pancreas is more rapid 
than that of the ventral. The anlages grow separately until they meet 




Fig. 61. — Photograph from Thyng. "Reconstruction from a human embryo at 7.5 
mm. (H. E. C. 256). X55 diams. D. chol., ductus choledochus. D. cyst., ductus 
cysticus. D.hep., ductus hepaticus. Pane, d„ pancreas dorsale. Pane, v., pancreas 
ventrale. St., stomach. Ves fel., vesical fellea." 




Fio. 62 



—(H. 187 Univ. of Minn. Collection.) Microphotograph of pancreas in embryo 
{loH mm. C. R. length) showing relation to stomach and left adrenal. 



posterior to the duodenum where they coalesce and continue develop- 
ment in one mass in the dorsal mesentery. The body and tail grow 
upward and to the left lie in the dorsal mesogastrium posterior to 



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126 E. J. HORGAN 

the stomach. As the stomach and dorsal mesogastrium change 
position the pancreas moves within the dorsal mesogastrium until its 
position is transverse when it becomes firmly fixed to the parietal peri- 
toneum of the posterior abdominal wall. In one embryo,* 26 mm., 
which I studied the dorsal and ventral anlages are fused. 

The primitive outpouchings are lined with a columnar epithelium 
similar to that in the duodenum. As the buds grow the epithelium 
develops branching ducts ramifying the connective tissue. The main 
duct of the dorsal pancreas opens into the duodenum while the main 
duct of the ventral pancreas opens into the common bile duct at the 
ampulla. When the dorsal and ventral anlages unite the main duct 



Ducta of WivstiM «n& S&ivtovitvi OVa-rvA grow? U*tnt1 



Common, bile duct-^ \ 




> Ant»toinoftvn{ iubuU 

V 

Ul»n& of LanflrffKan* 



Fig. 63. — Diagram of pancreas showing its histologic units. 

of the ventral pancreas makes a lateral anastomosis into the main 
duct of the dorsal pancreas. In this way the main duct of the ventral 
pancreas with the distal half of the duct of the dorsal pancreas forms 
the duct of Wirsung, and the proximal half of the duct of the dorsal 
pancreas is the duct of Santorini. When the embryo is from 26 mm. 
to 33 mm. in length, and the tail of the pancreas extends well out into 
the dorsal mesogastrium, branching tubules can be seen throughout 
the gland. No acini nor islets are to be seen at this stage and there is 
no evidence of lobulations. The connective tissue forms the major 
portion of the organ. At the end of the branches of the main duct the 
tubules have an enlarged bud. This bud branches and forms new 
* University of Minnesota Collections No. H 29. 



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THE HISTOGENESIS OF CARCINOMA 



127 



tubules until the acini begin to form by several buds at the tip of each 
tubule. After the acini have begun to form throughout the gland the 



A 




i 




\ ■ 


1 


1 


\ «y\ 


-«•»■ 



Fio. 64.— (H.187 Univ. of Minn. Collection.) Microphotograph of islet in embryo 

pancreas. 




Fig. 65. — (H.187 Univ. of Minn. Collection.) Oil immersion microphotograph of islet 

cells, embryo 158 mm. 

islet cells appear in the connective tissue along the small ducts. Pearce 

found masses of cells which he identified as islet cells in an embryo of 

54 mm. In the section of one embryo,* 158 mm. in length, in which I 

* University of Minnesota, Collection No. H.187. 



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128 



E. J. HORGAN 



examined the ducts, acini and islets were well developed. The islets 
stand out clearly in the loose connective tissue near the ducts. They 
are circular masses, the cells of which are not well differentiated. As 




Fig. 66. — (A135776). Microphotograph of islet in an infant aged eight months. 




Fio. 67. — (Al 35776). Oil immersion microphotograph of islet cells in an infant aged 

eight months. 

the glandular tissue grows into the connective tissue it envelops the 
islets. The connective tissue is derived from the mesodermal tissue 
of the dorsal mesentery (Fig. 62). 



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the histogenesis of carcinoma 
Histology 



129 



The embryology of the pancreas has been sufficiently studied in 
man and in species of lower vertebrates to establish the fact that all 
the histologic units develop from the same anlages. 




Fig. 68. — (A122722). Microphotograph of islet in pancreas of adult. 




Fio. 69. — (Al 22722). Oil immersion microphotograph of islet in pancreas of adult. 

The pancreas is a "mixed" epithelial gland composed of three 
separate and distinct histologic units each made up of differentiated, 
specialized epithelial cells: 



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130 



E. J. HORGAN 



1. The pancreatic ducts (of Wirsung, Santorini, the interlobar 
and intralobular ducts, and the anastomosing tubules of Bensley). 

2. The alveolar glands. 

3. The islets of Langerhans (Fig. 63). 

The pancreatic duct system. — The duct system in the pancreas is 
made up of one large duct, the duct of Wirsung, and an accessory duct, 
the duct of Santorini. From these ducts numerous highly branched 
tubules ramify the organ. The duct of Wirsung passes from the 
duodenal portion of the organ, where it opens into the ampulla of 
Vater, to the splenic portion. Throughout its entire length the first 
division of the tubules opens into it. These primary branches do not 




Fig. 70. — Diagram of peripancreatic lymphatic glands. 

enter directly; they pass obliquely through the connective tissue of 
the duct of Wirsung for a short distance. The terminal branches are 
rather tortuous; Bensley has shown that they have many anastomos- 
ing tubules. The main ducts (Wirsung and Santorini) are lined with 
a single layer of high columnar epithelium on a fine membrana propria; 
in some sections it is thrown up into folds. In the interlobular and 
intralobular and anastomosing tubules the epithelium is a single layer 
of columnar cells, gradually diminishing in height in the terminal 
branches. 

The alveolar glands. — Projecting out from the terminal ends of the 



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THE HISTOGENESIS OF CARCINOMA 



131 



tubules are the alveolar glands. These are branched tubular glands 
lined with a single layer of large secreting cells, pyramidal in shape, 
the apex of which points into the lumen of the acinus; the base, 
near which is a large circular nucleus, lies on a membrana propria. 
The cytoplasm is divided into two zones, granular and homogeneous; 
the granular zone at the apex is made up of the zymogen granules 
in a faintly staining protoplasm; the homogeneous zone is in the basal 
portion of the cell. The zymogen granules in the granular layer and 
the mitochondrial filaments in the homogeneous layer may be studied 
only by the use of special fixation and staining. The secreting acinic 





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V| 


i2$ 

qpsPte 



Fig. 71. — (A36163). Microphotograph of duodenal ulcer perforated onto pancreas 
showing marked connective tissue reaction in area of localized pancreatitis. 

cells receive their blood supply from a capillary network in the mem- 
brana propria. 

The islets of Langerhans. — These islets are small circumscribed 
masses of epithelial cells distributed throughout the entire organ, 
although they are more numerous in the splenic portion. Most of the 
islets are spherical, from 0.2 to 0.3 mm. in diameter, but they may be 
oval in shape. They have no duct connection, either with the pan- 
creatic tubules or with each other, but lie in close relationship to the 
tubules. The texture of the connective tissue separating them from 
the acini is very delicate. The arteries supplying the islets form a rich 
capillary cluster. The vessels do not enter through a hilus. Each 
islet has a number of small capillaries which pass in from the connective 



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132 



E. J. HORGAN 



tissue at different points on the surface. The arrangement of the 
efferent blood stream is the reverse. 

The islet cells are of two varieties, A and B. The A cells are the 
larger; they have a large elliptical nucleus with the chromatin in one 




Fio. 72. — (A611333). Microphotograph. Chronic pancreatitis. Interlobular fibrosis 

most marked. 




Fig. 73.— (120520). 



Microphotograph. Chronic pancreatitis. Interacinar fibrosis 
most marked. 



or two round clumps. In the cytoplasm there are many small granules. 
The smaller B cells are more numerous; they have a central nucleus 
which is circular and contains a larger amount of chromatin. 



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THE HISTOGENESIS OF CARCINOMA 



133 



Their cytoplasm is packed with small granules. These cells may be 
differentiated from one another and the granules stained only by the 
fixation and staining methods of Lane. In the sections the cells are 




Fig. 74.— (A58947). 



Microphotograph of hypertrophic islets. Stage of pancreatico- 
primary-adenocytoplasia. 




Fig. 75.— (Al 16521). 



Oil immersion microphotograph of hypertrophic islet. 
of pancreatico-primary-adenocytoplasia. 



State 



seen in irregular masses, in single, or in double cords. They lie in 
a delicate connective tissue among the loops of the capillary cluster 
(Figs. 64, 65, 66, 67, 68, and 69). 



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134 E. J. HORGAN 

Blood vessels. — The blood supply to the pancreas is through the 
splenic, hepatic, and superior mesenteric arteries. The main trunk 
of the splenic and hepatic aiteries each sends a number of branches. 
The superior pancreaticoduodenal and the inferior pancreaticoduodenal 
supply the head with a number of branches. The veins which are 
tributaries of the portal system follow the arteries. 

Lymphatics. — The lymphatics drain into the splenic, anterior, 
and posterior pancreaticoduodenal groups (Fig. 70). 

PATHOLOGY 

Technic. — The pancreatic tissue was examined grossly; blocks 
cut from the duodenal, central, and splenic portions of the pan- 




Fio. 76. — (A50276). Microphotograph of hypertrophic islet. Stage of pancreatico- 
secondary-adenocytoplasia. 

creas were sectioned and stained for microscopic study. The gross 
specimens had been preserved in neutral 10 per cent formalin 
solution. Blocks for microscopic study are preserved in 10 per cent 
formalin solution, Zenker's fluid with acetic acid, and Bensley's 
formalin-Zenker solution. Blocks from all the specimens which are 
preserved in formaldehyde solution were placed in a weak aqueous 
solution of ammonia for twenty-four hours and a few drops of strong 
ammonia added to the weaker alcohols when the tissues were being 
dehydrated; those preserved in Zenker's fluid with acetic acid and 



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THE HISTOGENESIS OF CARCINOMA 135 

Bensley's formalin-Zenker were dehydrated in the usual manner. 
The blocks were embedded in paraffin and several slides from each 
block were cut in series for the routine microscopic examination. 




Fio. 77. — (A50276). Oil immersion microphotograph of epithelial cells in hyper- 
trophic islet. Stage of pancreatico-secondary-adenocytoplasia. 




Fio. 78. — (A50276). Oil immersion microphotograph of epithelial cells in hyper- 
trophic islet. Stage of pancreatico-secondary-adenocytoplasia. 

Additional blocks and sections were cut when needed. A few frozen 
sections were made. Some sections were stained with Ehrlich's 
hematoxylin and eosin and Goodpasture's acid polychrome-methylene 



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136 E. J. HORGAN 

blue and eosin. Others were stained with phosphotungstic acid 
hematoxylin and Bensley's brasilin-water blue to differentiate the 
islet epithelium from the acinic epithelium. The blocks of tissue 




Fio. 79. — (A26398). Microphotograph of islet showing hypertrophic, hyper- 
plastic epithelial cells with migration of these cells through connective tissue capsule. 
Stage of pancreatico-tertiary-adenocytoplasia. 













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^■S^jSSr*^'-* 1 **! 


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Fio. 80. — (A26398). Microphotograph of periphery of islet showing hypertrophic, 
hyperplastic epithelial cells with migration of these cells through connective tissue 
capsule. Stage of pancreatico-tertiary-adenocytoplasia. 

which had been preserved in formaldehyde and treated with ammonia 
could be differentiated by these stains also. 

Chronic pancreatitis. — Chronic pancreatitis is an almost if not 



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THE HISTOGENESIS OF CARCINOMA 137 

a constant finding in association with gastric and duodena] ulcer; 
it is most marked, however, in the duodenal portion of the organ. 
The amount of pancreatic involvement and the degree of inflammatory 






Fig. 81. — (A26398). Oil immersion microphotograph of islet cells showing hyper- 
trophic, hyperplastic epithelial cells. Stage of pancreatico-tertiary-adenocytoplasia. 




Fio. 82. — (A50276). Microphotograph of islet showing hypertrophic, hyperplastic 
epithelial cells with migration of these cells through connective tissue capsule. Stage 
of pancreatico-tertiary-adenocytoplasia. 

reaction are dependent on the location and duration of the ulcer and 
the severity of the acute exacerbations. When the gastric or duodenal 
ulcer perforates on to the pancreas and an area of the pancreas becomes 



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138 



E. J. HOBOAN 



the base of the ulcer the marked local pancreatitis which develops 
gradually changes from an acute to a chronic form (Fig. 71). In 
addition there is usually a diffuse pancreatitis (Figs. 72 and 73). The 




Fig. 83. — (A50276). Microphotograph of periphery of islet showing hypertrophic, 
hyperplastic epithelial cells with migration of these cells through connective tissue 
capsule. Stage of pancreatico-tertiary-adenocystoplasia. 




Fig. 84. — (A50276). Microphotograph of islet cells showing hypertrophic, hyper- 
plastic epithelial cells. Stage of pancreatico-tertiary-adenocytoplasia. 

pancreatitis is manifested either by a lymphocytic infiltration or by 
fibrosis extending into the interlobular, interacinar and periductal 
connective tissue. 



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THE HISTOGENESIS OF CARCINOMA 



139 



Hypertrophy of the islets observed in the series of cases studied. 
In the microscopic examination of sections of the pancreas from 
the £62 cases that were selected for this study, hypertrophy of the 
islets in connection with a chronic pancreatitis was found in 48 
cases. When the histories of these 48 cases were examined, 
two important discoveries were made: first, none of them showed 
glycosuria in any of the urinalyses of twenty-four hour specimens 
made while the patients were under observation and examina- 
tion; second, 79.3 per cent of these were found to be cases in which a 
gastric or duodenal ulcer was found at operation or at necropsy. In 
the series of 262 cases which was selected for this study gastric ulcer 




Fio. 85. — (A142013, Aut. 269-1915). Advanced carcinoma of pancreas. 

was found in 71 ; in seventeen (25 per cent) the islets showed hyper- 
trophy. Duodenal ulcer was found in 61 cases; in nineteen (31 per 
cent) the islets showed hypertrophy. Gastric and duodenal ulcer 
were found associated in 11 cases; in two (18.1 per cent) the islets 
showed hypertrophy. Hypertrophy of the islets was also observed 
in 6 cases of gastric carcinoma, 2 cases of carcinoma of the rectum, 
one case of carcinoma of the sigmoid, and one case of cyst of the 
pancreas. 

Hypertrophy of the islets was observed grossly and in section from 
all portions of the gland. Grossly the largest ones appeared as creamy 



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140 



E. J. HORGAN 



white bodies. Microscopically the close relationship of these hyper- 
trophic islets to the ducts was very noticeable. They varied from 
slightly above normal to twenty times their normal size, the largest 
islet measuring 6 mm. in its greatest diameter. 

Microscopic pathology of hypertrophic islets. — There is a great 
variation in the size of the hypertrophic islets; they vary from 0.5 
mm. to 6 mm. in diameter. Most of them are round or oval, on 
section, although many do not conform to this shape. In a few cases 
examination of all the sections showed only a few hypertrophic islets 











Fig. 88. — (A142013, Aut. 269-1915). Microphotograph of section from advanced 
carcinoma of pancreas showing degenerating epithelial cells in dense fibrous tissue and 
fibrosis of islet. 

in each case; usually they were found in greater numbers. They are 
found in sections from all portions of the pancreas but in a few cases 
all which were observed were in the duodenal portion. Connective 
tissue in the islets is always increased and the capsule surrounding 
the islet is always thickened (Fig. 74). Hypertrophic and hyperplastic 
epithelial cells are found in these islets and in a few migration of these 
hyperplastic epithelial cells takes place; they pass through the three 
successive stages of neoplasia. 



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THE HISTOGENESIS OF. CARCINOMA 



141 



Primary cytoplasia.* — The arrangement of the cells in the islets 
in short single and double cordons and masses between the capillary 
loops is similar to the normal. Most of the epithelial cells of these 
islets are differentiated; some are hypertrophic and the outline of the 
cytoplasm in these is not well defined (Fig. 75). These islets have a 
thickened connective tissue capsule and a diffuse fibrosis throughout. 
They are 0.5 mm. to 1 mm. in diameter. The capillary blood vessels 
have slightly thickened walls. No leukocytes or lymphocytes are 




Fig. 87. — (Al 22622). Microphotograph showing hyalinized fibrosis of islet. 

to be seen nor is there any other evidence of an inflammatory process 
of the islets except a fibrosis. 

Secondary cytoplasia. — The cordons formed by the epithelial cells 
are more marked than in the normal islet. Most of the cordons are 
formed by single rows of epithelial cells, a few by double rows. In 
the sections these cordons follow the contour of the blood vessels 
and where the vessels are sectioned transversely the cordons encircle 
them. The epithelial cells are undifferentiated or partially differenti- 
ated. Some of the undifferentiated cells are hypertrophic. The 

•MacCarty's terminology of stages of neoplasia: 

Primary cytoplasia = Hypertrophy of regenerative cells plus presence of 
differentiated cells. 

Secondary cytoplasia = Hyperplasia of regenerative cells plus absence of differen- 
tiated cells, with or without partial differentiation. 

Tertiary cytoplasia = Hyperplasia of regenerative cells plus migration, with or 
without partial differentiation. 



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142 E. J. HORGAN 

number of epithelial cells has increased markedly but all the cells are 
confined within the connective tissue capsule (Figs. 76, 77 and 78). 
Some of these hypertrophic islets with hyperplasia of the epithelial 
cells are very large (0.6 mm. to 1.5 mm.). The capsule is of dense 
fibrous connective tissue and fibrosis is diffuse throughout the islet. 
The capillary blood vessels have increased in proportion to the size 
of the islets and the vessel wall is thickened. There is no evidence 
of inflammation except fibrosis. 

Tertiary cytoplasia. — The cordons are not well defined; most of 
the cells are in masses. The epithelial cells are undifferentiated; 
some, however, in some islets show partial differentiation. They are 
hypertrophic and hyperplastic, there being a marked increase in the 
size and number. In the center of some of the islets there is an area 
of cellular debris as the result of cellular disintegration; a few nuclei 
can be identified in this area. Migration of the epithelial cells through 
the connective tissue may be seen at the periphery. This migration 
of the epithelial cells is evidence of a carcinoma (Figs. 79 to 84). These 
islets are very large, the largest being 4mm. by 6 mm. Proliferation 
of the connective tissue is very marked throughout the islet and the 
capsule is thick and densely fibrous. Bands of fibrous tissue pass out 
from the capsule of the islet into the interacinar and interlobular 
connective tissue. The blood vessels are very large, but their size is 
in proportion to the size of the islet, and their walls are thickened. 

Discussion 

The islet areas in the pancreas were first described by Langerhans* 
who considered them to be the end apparatus of nerve fibers. From 
the collective embryologic, cytologic, and histologic studies of later 
workers, foremost among them Renaut, Laguesse, Opie, Lane, Lewis, 
Thyng, Dewitt, and Bensley, it has been well established that the 
islets are, histologically, a definite epithelial unit of the pancreas 
developed from the epithelium of the primitive anlages, without 
duct connection, with a rich capillary blood supply, and a hormone- 
secreting function. 

Hypertrophy of the islets, and adenomas of the islets, are the 
only conditions reported in the literature which could be considered 
precancerous. Hypertrophy has been reported mostly in connection 
with diabetes. It is not characteristic of diabetes, however, nor is it 



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THE HISTOGENESIS bF CARCINOMA 143 

to be found in all cases of diabetes. Nichols, Helmholtz, and Cecil 
have reported cases of a single hypertrophied islet in the pancreas. 
Nichols and Helmholtz each considers his case to be an adenoma while 
Cecil reports his case an hypertrophy of the islet. 

After reviewing the literature I find that most writers classify 
carcinoma of the pancreas either as alveolar or canalicular. 

In 1903, Fabozzi reported his study of the pancreatic tissue taken 
from 5 patients who had died from carcinoma of the pancreas and 
tried to establish from these the histogenesis of carcinoma of the 
pancreas. His deduction is that all carcinomas of the pancreas have 
their origin in the islets. His illustrations are diagrammatic, and his 
descriptions are not sufficiently conclusive to be accepted by later 
writers. 

It is not reasonable to assume that all neoplasms in a mixed gland, 
like the pancreas, originate in one only of its three epithelial units. 
It is more logical to assume that a neoplasm may originate in any one 
of the epithelial units, the ducts, the acini, or the islets. From a 
biopathologic point of view the histogenesis of neoplasia of the pancreas 
should be studied in each of these. Under suitable pathologic condi- 
tions, each epithelial unit could be expected to produce undifferentiated 
cells from its germinative tissue; but the study must be made from the 
tissues which show the changes antecedent to carcinoma. When 
neoplasia is well advanced or has caused death, it is impossible to 
establish the site of origin or the successive pathologic changes from 
the tissue removed at operation or at necropsy; it is because patholo- 
gists have tried to prove the histogenesis from tissue removed at 
necropsy, after malignancy has caused death, that the histogenesis 
of carcinoma of the pancreas has not been established (Fig. 85). In 
a microscopic study of advanced carcinoma of the pancreas we find 
small masses of cells in the dense fibrous connective tissue. In their 
form and arrangement they may resemble small ducts, or acini, but 
if carefully scrutinized they will prove to be groups of degenerating 
cells. They are epithelial cells, but whether they are degenerating 
acinic cells or degenerating cells of neoplasia cannot be determined 
(Fig. 86). 

The histogenesis of carcinoma of the pancreas must be studied 
from pc rtions of the pancreas which are too small to be recognized in 
the gross specimen as carcinoma. For this reason I selected for the 
study of the early neoplastic changes a series of cases which show 



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144 E. J. HORGAN 

chronic inflammation. In the course of the investigation I found a 
definite hypertrophy and hyperplasia of the islets of Langerhans. 
This condition was found in about 25 per cent of the cases of chronic 
interacinar and interlobular pancreatitis which was associated with 
chronic gastric and chronic duodenal ulcer. In these hypertrophic 
islets hypertrophy, hyperplasia, and migration of the cells were 
observed. 

In the hypertrophic islets I found hypertrophic differentiated cells. 
Accompanying this cellular hypertrophy the connective tissue within 
and surrounding the islets had increased to protect the adjacent cells 
from encroachment. 

In similar islets I sometimes found also hyperplasia of undiffer- 
entiated epithelial cells. These undifferentiated cells, however, are 
distinctly confined within the dense capsule of the islet. 

In some of the hypertrophic islets I found hyperplastic undiffer- 
entiated cells migrating through the capsule, a condition which is 
undoubtedly carcinoma. 

These three graphic descriptions apparently represent the stages 
of neoplasia as described by MacCarty in other epithelial tissues. 

Simple fibrosis and sometimes hyalinized fibrosis were the only 
purely inflammatory reactions found in this series (Fig. 87). 

The biologic reactions in the epithelial cells of the islets in the 
pancreas conform to those that have been observed in epithelial cells in 
other tissues. MacCarty has pointed out that each organ should be 
studied from the standpoint of each histologic unit; that each his- 
tologic unit must be considered alone from the standpoint of regenera- 
tion in all its phases; and that each phase should be named with a 
descriptive term applicable to that tissue; these biopathologic reac- 
tions of the epithelium of the islets in the pancreas might then be 
described as follows: 



Pancreatico- 



primary 

secondary \ adeno-cytoplasia 



tertiary 

These descriptive terms are expressive of the successive biopathologic 

reactions in the regeneration of cells in neoplasia in the islets of the 

pancreas. 

BIBLIOGRAPHY 

1. Bensley, R. R.: Studies on the pancreas of the guinea pig. Am. Jour. Anat., 
1911, xii, 297-388. Structure and relationship of the islets of Langerhans. Harvey 
Lectures, 1914-15, x, 250-269. 



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THE HISTOGENESIS OF CARCINOMA 145 

2. Cecil, R. L.: On hypertrophy and regeneration of the islands of Langerhans. 
Jour. Exper. Med., 1911, xiv, 500-519. 

3. Cecil, R. L.: Concerning adenomata originating from the islands of Langer- 
hans. Jour. Exper. Med., 1911, xii. 595-603. 

4. Dewitt, L. M. : Morphology and physiology of areas of Langerhans in some verte- 
brates. Jour. Exper. Med., 1906, viii, 193-239. 

5. Fabozzi, S.: Ueber die Histogenese des primaren Krebses des Pankreas. Beitr. 
z. path. Anat. u. z. allg. Path., 1903, xxxiv, 199-219. 

6. Gelle: Le cancer primitifdu pancreas; etude histologique et physiopathologique. 
Arch. d. mid. exp. et d'anat. path., 1913, xxv, 1HL9. 

7. Laguesse, E.: Le Pancreas. Rev. gen. d'histologie, 1906-8, ii, 1-288. 

8. Lane, M. A.: The cytological characters of the areas of Langerhans. Am. Jour. 
AnaU 1007, vii, 409-422. 

9. Langerhans, P.: Beitrage zur mikroskopischen Anatomie der Bauchspeichel- 
drtise. Inaug. Diss., Berlin, 1869. Quoted by Lane. 

10. Lewis, F. T.: Development of the pancreas. In: Keibel, F., and Mall, F. P.: 
Manual of Human Embryology; Philadelphia, Lippincott, 1912, ii, 429-445. 

11. MacCarty, W. C: Pathology and clinical significance of gastric ulcer. Surg., 
Gynec. and Obst., 1910, x, 449-462; The histogenesis of cancer of the breast and its 
clinical significance. Surg., Gynec. and Obst., 1913, xvi, 441-459; The histogenesis of 
carcinoma in ovarian simple cysts and cystadenoma. Collected Papers of the Mayo 
Clinic, Philadelphia, Saunders, 1913, v, 380-390; Clinical suggestions based upon a 
study of primary, secondary (carcinoma?) and tertiary or migratory (carcinoma) epi- 
thelial hyperplasia of the breast. Surg., Gynec. and Obst., 1914, xviii, 284-989; 
Precancerous conditions. Jour. Iowa State Med. Soc., 1914-1915, iv, 1-11; The histo- 
genesis of cancer of the stomach. Am. Jour. Med. Sc., 1915, cxlix, 469-476; New facts 
about cancer and their clinical significance. Surg., Gynec. and Obst., 1915, xxi, 6-8; 
The biological position of the carcinoma cell. Pan.- Am. Surg, and Med. Jour., 1915, xx; 
The evolution of cancer. Collected Papers of the Mayo Clinic, Philadelphia, Saunders, 
1915, vii, 903-917; A new classification of neoplasms and its clinical value. Am. 
Jour. Med. Sc., 1916, cli, 799-806; Cancer's place in general biology. Am. Naturalist, 
1918, 800-818. 

12. MacGrath, B. F.: Cancer of the prostate. Jour. Am. Med. Assn., 1914, Ixiii, 
1012-1018. 

13. Opie, £. L.: Disease of the pancreas, its cause and nature. Philadelphia, 
Lippincott, 2d ed., 1910, 387 pp. 

14. Pearce, R. M.: The development of the islands of Langerhans in the human 
embryo. Am. Jour. Anat., 1902-3, ii, 445-455. 

15. Renaut: Quoted by Lane. 

16. Thyng, F. W.: Models of the pancreas in embryos of the pig, rabbit, cat and 
man. Am. Jour. Anat., 1908, vii, 505-519. 



•19-10 



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THE UTILITY OF THE RUBBER TUBE IN INTESTINAL 

SURGERY* 

D. C. BALFpUR 



The difficulties which not infrequently confront the surgeon in 
carrying out operations on the large and small intestine are to a con- 
siderable degree overcome by his familiarity with the established prin- 
ciples of intestinal surgery, his ability to employ technical methods of 
proved value and to utilize the various mechanical devices which, 
in the development of the surgery of the gastro-intestinal tract, have 
been devised to meet special conditions arising during the course of 
the operation. Of such mechanical devices the rubber tube deserves, 
I believe, more general and favorable recognition than is at present 
accorded it. Its usefulness in certain intestinal operations has been 
so evident, and the result of such operations so gratifying, that it seems 
advisable again to draw attention to these facts by presenting abstracts 
of case reports which are representative of some of the conditions 
under which we have employed the rubber tube, and which illustrate 
the utility of the tube in intestinal surgery. 

Such operations as resections of the sigmoid, rectosigmoid juncture, 
or upper rectum for malignancy, are and always will be frequently of 
considerable technical difficulty and of relatively high risk. In our 
experience in the Mayo Clinic the rubber tube has been an important 
factor in minimizing such difficulties and risks, and it was in certain 
cases in this group that the tube was first employed as an aid in accom- 
plishing a safe axial anastomosis. Its value under these circumstances 
had been recognized for several years; Rutherford Morison, Lockhart 
Mummery, and other English surgeons, were early advocates of its 
merit, and it had been employed in the Mayo Clinic for some time prev- 
ious to 1910, when I described the technic of "tube-resections" of the 
sigmoid as then carried out in the clinic. Since that time certain modi- 
fications in the operative" technic then described have been found 
advantageous; and, as is so frequently true, the higher efficiency which 

* Reprinted from Surg. Gynec., and Obst., 1920. 
146 



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THE RUBBER TUBE IN INTESTINAL SURGERY 



147 



has come from such improvement in technical methods has made possi- 
ble not only better results, but also a definite increase in "operability." 
We have accepted as operable and successfully removed malignant 
tumors of the lower sigmoid or upper rectum, the operability of which, 




Fig. 88. — Beginning of posterior suture line. 

without the aid of the tube in the operation, would be at least highly 
questionable. 

The tube used in such cases is Y± inch in diameter with } i inch caliber 
with a lateral eye about 1 inch from its upper end. The resection having 
been made, the tube is introduced through the open end of the lower 



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148 



D. C. BALFOUR 



segment and passed by the surgeon downward through the rectum 
and anus; it is there secured by an assistant and tracted upon until 
the upper end of the tube is brought below the level of the cut end of 
the lower segment. The two ends of bowel are now approximated, 
properly aligned, and fixed by a stay suture in the middle of one lateral 



•,:A 



Calo'ni 'iu.ciLve tru 
I t-u.bht.-r tube 



LirLe of 
a.rta.s-fco-musi.3 . 




Fig. 89. — Anastomosis completed; bowel ready for invagination. 

wall and a second stay suture at a corresponding point at the opposite 
side. At this latter point a heavy chromic catgut suture is begun. 
This suture is introduced from the mucous side and includes the mucous 
and musculai layers of the intestinal wall and is continued posteriorly 
in this manner until the stay suture, which was first placed, is reached. 
Our experience has been that, if No. 2 chromic catgut is used andspecial 



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THE RUBBER TUBE IN INTESTINAL SURGERY 



149 



care is taken to approximate the mucous membrane so that it does not 
extrude outside the bowel wall, a most satisfactory closure posteriorly 
can be secured (Fig. 88.) When the circular anastomosis is completed 
in the usual manner by a continuation of this chromic catgut suture, 
the tube is passed up the bowel by the assistant until it reaches a point 




Fig. 90. — Final relationship of the bowel and rubber tube (diagrammatic). 

from 3 or 4 inches to 1 foot above the level of the anastomosis. The cor- 
rect height of the tube must be gauged by the ease with which it takes its 
position in the upper segment. The tube, resting in its best position 
in the upper segment, is secured by a suture of heavy catgut placed close 
to the anastomosis line, so that the suture will be in vaginated with the 
anastomosis later (Fig. 89). The invagination, which we believe to be 



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150 



D. C. BALFOUR 



a very important feature of the operation, is then made by grasping 
the lower segment with fine toothed forceps at a point of about 1 inch 
below the line of anastomosis; and by means of these forceps the lower 
segment is supported while the assistant pulls downward on the tube 
until the anastomosis line is drawn into the lower segment, and the anas- 



Cat gub 

bou/el 




' Fio. 91. — Operation completed. 

tomosis is completely covered (Fig. 90) . The loose ring of the lower 
segment is then fixed to the upper segment by three or four interrupted 
sutures (Fig. 91). The bowel at the site of the anastomosis then has the 
same appearance as that of a small intussusception. In some cases 
it is not possible to produce such an invagination because of the extent 
of the resection, and in some instances it is not even possible perfectly 



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THE RUBBER TUBE IN INTESTINAL SURGERY 151 

to unite the two ends of the bowel over the tube. It is surprising, how- 
ever, to observe the excellent immediate and ultimate results in such 
unsatisfactory cases; and even in cases in which a visible defect in the 
line of the anastomosis was present (usually on the posterior side) a 
satisfactory convalescence has ensued. When a fecal fistula does occur 
spontaneous closure can be anticipated. In the majority of cases it 
is quite safe to close the abdomen without drainage. 

REPORT OF CASES 
RESECTION FOR CANCER OF THE SIGMOID 

Case 1 (A261807). Miss E. E. H„ aged 26, presented herself at the 
clinic Feb. 27, 1919. She gave a history of having had symptoms 
suggestive of a partial obstruction of the large bowel, beginning 
December, 1918; these symptoms became more definite and severe 
until January, 1919, when obstruction was complete and operation im- 
perative. The surgeon, finding the obstruction in the sigmoid due to 
a mass apparently malignant, ^considered any attempt to remove the 
tumor inadvisable and performed a colostomy. Six weeks later the 
patient arrived at the clinic in fairly good physical condition and with 
only a moderate weight loss. Examination showed a well functioning 
colostomy and a mass in the left pelvis which could be easily outlined, 
both by vagina and by rectum. An x-ray examination revealed an ob- 
struction of the colon about 5 inches above the rectosigmoid. The ab- 
sence of any evidence of metastasis, the good condition of the patient, 
and, particularly, our previous experience in such cases, led us to ad- 
vise exploration. March 6, 1919 an abdominal exploration wa^s made 
(W. J. Mayo). An incision 1 inch to the left of the midline gave easy 
access to the growth in the sigmoid. The growth proved to be a con- 
stricting cancer, of the napkin ring variety, situated about 4 inches above 
the rectosigmoid juncture. Resection seemed feasible and, after the 
separation of the colostomy from the abdominal wall, a portion of the 
sigmoid, including both the colostomy and the growth, was removed. 
Because of the firm attachment of the sigmoid to the left ovary and 
tube, it was necessary to remove both of these structures. An end-to- 
end union was then accomplished over a tube in the manner described 
above; the former abdominal incision was widely excised before closing, 
and two rubber tissue drains were carried down to the site of the anas- 
tomosis. The patient had a most satisfactory convalescence; the 



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152 D. C. BALFOUR 

tube was removed on the eighth day, and both the new incision and 
the former incision were healed when she left for home three weeks 
after operation. Her present condition is excellent; and although 
malignancy at such an age is associated with a gloomy prognosis, some 
prospect of cure can be entertained. 

Case 2 (A185641). Mrs. H. C. L., aged 41, came to the clinic Feb. 
14, 1917 giving a history of symptoms of obstruction of the sigmoid 
over a period of the past twenty-two months. A mass could easily 
be identified in the suprapubic region, and on bimanual examination 
it proved to be in the left pelvis. Exploration was carried out Feb. 
24, 1917 (J. C. Masson). A cancer of the left rectosigmoid was found, 
the mass being adherent to the uterus, the left broad ligament, and the 
left lateral wall of the pelvis. It had all the characteristics of a malig- 
nant process and was clearly inoperable. Colostomy was done and 
radium treatments advised. In January, 1918 the patient had 1600 
mg. hours, in August, 1900 mg. hours, and in January, 1919, 4200 mg. 
hours. At each examination the mass was distinctly smaller, with a 
corresponding decrease in symptoms, such as pain and discharge. In 
November, 1919 the patient returned to the clinic, requesting to have 
the colostomy closed. She was in excellent general health, weighed 224 
pounds, and the absence of symptoms showed, at least, that the former 
malignant mass was inactive. On examination of the lower segment 
through the colostomy opening, the finger could not be passed because 
of the contraction which had taken place beyond the site of the former 
growth. Bimanual examination showed a small nodular movable mass 
high in the pelvis. A second operation was, therefore, performed 
November 15 (J. C. Masson). The portion of the sigmoid in w r hich 
the radium had been used was in an atrophic condition, with marked 
thickening of the intestinal walls and, because of the extent of this 
induration, it was necessary to remove about 14 inches of the colon; the 
resected portion contained the colostomy and the thickened bowel. 
The operation was unusually difficult because of the short lower seg- 
ment, the patient's obesity, and the fixity of the segments of intestine. 
The anastomosis, however, was finally accomplished over a rubber tube 
by interrupted sutures of chromic catgut, the bowel being intussuscep- 
ted about 1 inch. The anastomosis was carefully protected by suturing 
the omentum over it, and the uterus fixed to the anterior aspect of the 
anastomosis. It was difficult to determine from the gross appearance 
of the sigmoid whether or not any active cancer cells were present; 



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THE RUBBER TUBE IN INTESTINAL SURGERY 153 

and it was very interesting, important, and gratifying to find that 
repeated pathologic examinations did not show any evidence of malig- 
nancy. The wound was closed without drainage; the patient made 
a satisfactory convalescence, and left for her home Dec. 17, 1919. 

RESECTION FOR DIVERTICULITIS OF THE SIGMOID 

Case 3 (A35613). Mrs. J. G. F., aged 52, had had an exploratory 
operation elsewhere in March, 1909 because of symptoms referable to 
the sigmoid region; and at the exploration three diverticula were ob- 
served in the sigmoid over an area of about 2 H inches. A conservative 
operation was done, but leakage developed at the site of the operation 
and a fecal fistula persisted and was chiefly the reason for which the 
patient presented herself at the clinic. Exploration (the closure of the 
fistula being the primary object) was clearly advisable, and was 
done March 24, 1910 (C. H. Mayo). A diverticulitis of the sigmoid 
was found which was adherent to the small intestine and a small 
abscess in the abdominal wall. After the separation of these various 
adhesions, the sigmoid was resected and an anastomosis carried out 
by the tube method, as described above. The patient made a most 
satisfactory convalescence and has remained well. 

The tube, then, can be used in certain cases of diverticulitis in a 
manner similar to that described, but it is not employed so frequently 
as in operations for cancer of the sigmoid because of the fact that the 
mass in diverticulitis is usually in the upper sigmoid and can be mobi- 
lized without much difficulty. Resection, therefore, is usually made in 
diverticulitis by the Mikulicz three-stage method, and when immediate 
axial anastomosis is indicated the procedure is not particularly difficult. 

In cases in which primary resection is advisable, a satisfactory and 
safe method to employ is that suggested by C . H . Mayo. After a circular 
anastomosis has been accomplished in the usual manner, the entire 
anastomosis line is drawn through an opening made at a suitable point 
in the omentum and attached to the peritoneum at the incision in such 
a way that the suture line shows after the peritoneum is closed. The 
wound can then be closed without drainage, or, if preferred, with mural 
drainage. This method has given us most satisfactory results. The 
general abdominal cavity is effectively walled off by the omentum; and, 
should any leakage occur, such drainage has no difficulty in finding its 
way into the incision. 



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I 



154 D. C. BALFOUR 

REPAIR OF FECAL FISTULA 

Case 4 (A291805). Mrs. M. A. H., aged 46, came to the clinic Oct- 
3, 1919 because of a fecal fistula. An abstracted history shows that she 
had been perfectly well until about two years before, when she had an 
attack of severe abdominal pain in the left lower abdomen lasting three 
or four hours, which was to some extent relieved by hot applications. 
Until May, 1919 she continued to have these attacks, which usually 
lasted about three or four hours and occurred at intervals of three or 
four months. In May, 1919 an attack developed as usual apparently, 
but could not be relieved by the usual measures, and after it had con- 
tinued for about a week the patient was operated on elsewhere and 6 
inches of the sigmoid resected, anastomosis being made by means of the 
Murphy button. The pathologic report made at the time on the speci- 
men excised was "small round-cell sarcoma." The patient developed 
a fistula three days after the operation, suffered a great deal of general 
pain throughout the abdomen, and failed to show any improvement. 
In the physical examination carried out at the clinic on her arrival the 
chief finding was a mass in the right pelvis, apparently on the rectal 
shelf, of a rather nodular character, and considered to be a recurrence 
of the malignant process. It seemed advisable to explore, however, and 
to close the fistula if feasible. Exploration was carried out Oct. £4, 
1919 (W. E. Sistrunk). Fortunately no evidence of malignancy could 
be demonstrated. The mass, which could be palpated before opera- 
tion, proved to be an induration due to scar tissue which appeared to be 
the result of the previous operation. The dissection of the fistulous 
tract led to the site of the former operation and at this point in the sig- 
moid there was considerable thickening and the bowel was firmly ad- 
herent to the posterior wall of the uterus. Having liberated the bowel 
it was necessary to excise the segment of indurated sigmoid, which was 
a matter of some difficulty because of the firm inflammatory changes 
which had taken place. Anastomosis was made over a tube in the 
typical way, the tube being of particular assistance because of the 
fixity of the segments of bowel. The patient had a very satisfactory 
convalescence; a slight difficulty in the passage of fecal matter through 
the tube was overcome by the manipulation of a catheter through the 
lectal tube. 



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THE RUBBER TUBE IN INTESTINAL SURGERY 155 
USE OF TUBE ALONE IN CHRONIC AND SUBACUTE OBSTRUCTION 

Case 5 (A177159). Mrs. J. D., aged 39, came to the clinic Nov. 6, 
1916, complaining of attacks at irregular intervals of great abdominal 
distress due to an enormous distention of the abdomen with gas, with 
marked respiratory distress and cardiac pain. The attacks lasted 
frequently for from two to four days and were associated with a great 
deal of pain in the joints, especially the legs and shoulders. The pa- 
tient was rarely entirely free from distress, although there were periods 
of from twelve to twenty-four hours when she was reasonably comforta- 
ble. Gas was expelled by rectum and through a fistula which existed 
in one of the abdominal incisions. The significant findings in the 
physical examination were the marked abdominal tympany, associated 
with visible intestinal peristalsis, four scars of previous abdominal 
operations, and general evidences of chronic infection, particularly in 
the joints of the feet and hands. The history leading up to the pres- 
ert condition was, chiefly, that four years before, following a severe 
attack of abdominal pain, the appendix, uterus, and some gallstones were 
removed elsewhere. Four weeks later it was necessary to do an ileo- 
sigmoidostomy because of obstruction. For the following years the 
patient had comparatively good health, but finally the intestine be- 
came obstructed again with formation of the fecal fistula and in May, 
1916 she was again operated on. The fistula was closed and several 
loops of small intestine liberated. Following this operation the pa- 
tient continued to have the symptoms which have been described. 
At operation Nov. 17, 1916 (E. S. Judd) a condition of general intestinal 
paresis was found. No point of definite obstruction could be deter- 
mined. The small intestine, the cecum, and the transverse and descend- 
ing colon were especially dilated. Because of the repeated operations 
and the general character of the obstruction, there was apparently 
no method of anastomosis by which a good result could with certainty 
be accomplished. A long rectal tube was passed per rectum through 
the existing anastomosis and continued for about 18 inches into the small 
intestine. Immediately a great quantity of gas and fecal matter passed, 
and it was decided to leave the tube in as long as possible in the hope 
that in the inevitable reformation of adhesions it would act in the rdle 
of a splint, and would support the bowel so that disabling deformity 
would not later occur. In a recent report the patient states that she 
has remained well and free from the intestinal disturbances for which 
the operation was carried out. 



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156 D. C. BALFOUR 

This case is a striking illustration of the value of the tube in those 
cases of chronic or subacute obstruction developing as a late result 
after repeated operations. When the tube can be employed in such 
cases the uncertainty which is so frequently felt by the surgeon is 
converted into an assurance that the segment of the intestine which 
has been supported by the tube will be so molded in the new mat of 
adhesions that future obstruction at that point is most unlikely to 
occur. 

A case similar in some features to the foregoing, and having added 
points of interest, is the following: 

Case 6. (A253595). Miss M. G., aged 20, came to the clinic Dec. 
16, 1918 with a complaint of suffering daily from great accumulation 
of gas. This bloating usually came on between 4 and 6 in the after- 
noon; belching hugh quantities of gas and slight vomiting usually 
gave partial relief. On two occasions the patient had attacks of 
abdominal cramps, apparently of great severity; these were also re- 
lieved when the gas was expelled. The patient was a rather unhealthy 
looking girl, but no evidences of gross disease could be determined. 
The abdomen was greatly distended and repeated purgation together 
with daily doses of belladonna failed to make any appreciable change 
in the distension. An x-ray examination showed a hugely dilated 
stomach, the bismuth remaining in the stomach for three days, and, 
although it was not possible to demonstrate positively that a pyloric 
lesion was present, surgical interference seemed indicated. Jan. 2, 
1919 an abdominal exploration was done (D. C. Balfour). General 
exploration immediately confirmed the physical examination and the 
x-ray findings. The stomach was dilated to great size, the lower 
border reaching almost to the symphysis. No actual lesion could be 
found at the pylorus to account for the obstruction, it apparently 
being due to a mass of adhesions extending from the hepatic flexure 
to the duodenum and pylorus. Beside this tremendous dilatation 
of the stomach was a dilatation of the proximal half of the large bowel; 
this portion of the colon was doubled on itself by another wide band 
of adhesions, stretching from the middle of the ascending colon to the 
left half of the transverse colon. The proximal half of the colon was 
dilated to about 10 or 11 inches; the distal half was little more than noi- 
mal size. The primary cause of these two conditions was not evident. 
In the absence of any visible lesion, the most plausible explanation 
seemed to be that either a congenital abnormality in the rotatioa 



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THE RUBBER TUBE IN INTESTINAL SURGERY 157 

of the colon or some inflammatory process in childhood had left the 
colon in such a relationship that strong bands of adhesions were de- 
veloped to the point of causing chronic obstruction and producing 
secondarily, from traction and trauma, the adhesions to the pylorus 
and duodenum. It seemed unwise, in any event, to attempt any 
prolonged investigation (because of the risk to the patient and the 
uncertainty of securing any important information) to learn the cause 
of the condition and this decision was strengthened by the fact that 
it was perfectly clear what was necessary to be done to meet the symp- 
toms of which the patient complained. Gastroenterostomy was 
first performed, followed by colocolostomy, the latter anastomosis 
being made between the tremendously distended cecum and the normal 
sigmoid. A large rectal tube was passed through the anus, rectum, and 
anastomosis until the end was about 1 foot above the level of the coloco- 
lostomy. The patient had a satisfactory convalescence, and has had 
complete relief from all the symptoms of which she complained. 

RESECTION OF TRANSVERSE COLON 

Case 7. (A263828). Mrs. N. W., aged 50, came to the clinic 
in March, 1919, chiefly because of discomfort which had begun in the 
epigastrium about three weeks before. This discomfort was usually 
associated with nausea, but vomiting occurred on only one occasion. 
The pain had never been severe and radiated only to the lower ab- 
domen; temporary relief was secured on defecation. There had been 
no diarrhea nor abdominal colic. The patient stated that for a period 
of thirty years she had been distressed occasionally by a dull, 
bloated feeling in the epigastrium, usually immediately after taking 
food. The character of the distress, which had developed recently, 
its radiation to the lower abdomen, and the relief on bowel movement, 
suggested the possibility of intestinal obstruction. An x-ray of the 
colon demonstrated a cancer involving the hepatic flexure and the 
first part of the transverse colon. Exploration was, therefore, advised 
and carried out March 4, 1919 (J. D. Pemberton). A huge cancer of 
the transverse colon was found involving the glands in the transverse 
mesocolon. The growth had penetrated the serosa of the bowel and 
there was free fluid in the abdomen. A hard nodule at the anterior 
edge of the liver was excised and found to be a mass of gallstones 
which had become encysted following a perforation of the fundus of 



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158 D. C. BALFOUR 

the gallbladder into the liver substance. A resection of the trans- 
verse colon well away from the tumor was done and a direct end-to-end 
anastomosis made by the C. H. Mayo method, followed by a partial 
cholecystectomy with drainage of the gallbladder. At the completion 
of the operation, the anus was dilated and the rectal tube inserted and 
left in until the twelfth day. The patient made a satisfactory con- 
valescence and has shown no evidence of a recurrence up to the present 
time. 

It is advisable under certain conditions to provide a safety valve 
for the large intestine to prevent spasm of anal or rectosigmoid sphinc- 
ters at a time when distension of the colon should be guarded against. 
A rectal tube serves such a purpose excellently and may often be 
resorted to in place of a colostomy or appendicostomy. 

CLOSURE OF COLOSTOMY 

Case (A253976). Rev. J. J. L., aged 48, came to the clinic Decem- 
ber, 1918 because of a tumor in the left lower abdomen, attacks of 
pain, and partial obstruction for the last two years. The most 
recent attack was about one week before the examination in the clinic; 
the tumor had first been noted at this same time. Three months 
before he had had a severe hemorrhage of bright red blood; two other 
such spells of bleeding had occurred up to the time of his examination. 
A diagnosis of duodenal ulcer had been made elsewhere. The phys- 
ical examination disclosed a hard mass which could be readily pal- 
pated both through the abdominal wall and bimanually. The x-ray 
confirmed the clinical diagnosis of cancer at the rectosigmoid juncture. 
The patient was operated on Dec. 12, 1918, (W. J. Mayo). A Miku- 
licz three-stage operation was done. A satisfactory convalescence 
ensued, and January 11 a clamp was applied to the spur of the sig- 
moid. The further convalescence placed this patient in the small 
group of patients in whom the bowel does not completely close after 
the routine three-stage Mikulicz operation, and April, 1919 he returned. 
An extraperitoneal closure of the colostomy was done over a Smithies 
stomach tube, which was introduced through the colostomy and 
pushed down through the anus, with the upper end about 2 inches 
above the point where the bowel was closed. This procedure com- 
pleted the satisfactory result; the patient is at present apparently in 
perfect health. 



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THE RUBBER TUBE IN INTESTINAL SURGERY 159 

Ineffective attempts to close colostomies are occasionally met with. 
Successful closing sometimes requires enough suturing of the opening 
in the bowel to constrict the lumen beyond what appears to be the limit 
of safety. The tube serves a useful purpose by preventing further 
contraction; and by conveying gases and fecal matter past the point 
of closure it gives the best possible condition under which healing 
may occur. In such cases the tube is introduced through the colos- 
tomy and passed out of the anus, leaving the upper end about 8 or 
4 inches above the point of closure; it is removed in about ten days. 

DISCUSSION 

The foregoing abstracted cases illustrate the wide utility of a 
rubber tube in intestinal surgery, and I am convinced that further 
experience in extending its use will show that in the past we have occa- 
sionally overlooked its value because we have failed to recognize, or 
have forgotten, certain sound principles in the surgery of the gastro- 
intestinal tract. Such principles could have been well carried out in 
certain cases by the use of the rubber tube. The mechanical func- 
tions of the tube are chiefly called upon in its employment in axial 
anastomosis, closure of colostomy, and fecal fistula repair. In such 
cases, its first service, as I have pointed out, is the prevention of gross 
leakage from an insecurely closed intestine. We have repeatedly met 
with cases in which the extent of bowel resected has been so great 
or the segment so fixed, or for both reasons, that approximation has 
been made difficult and an unsatisfactory union has resulted, on the 
mesenteric side particularly. When, however, such an anastomosis 
has been made over a good sized rubber tube the results have been 
unmistakable evidence that the tube, immobilizing the two segments of 
bowel as it does, gives protection against leakage, because of the se- 
curity against undue tension, with the possible results of a weakened 
or ruptured suture line. Fecal fistulas which occur under such circum- 
stances have been insignificant, as a rule healing spontaneously in a 
short time. 

A further and most important mechanical function of the tube is 
observed in its actions as a splint. The danger of postoperative ob- 
struction is always to be considered in those cases in which extensive 
scar due to previous operative interference or the adhesions of inflam- 
matory exudates are present, for, in the inevitable reformation of ad- 



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160 D. C. BALFOUR 

hesions, the bowel may be fixed in such a manner that immediate or 
later obstruction is possible. In such cases, the tube within the bowel 
prevents any kinking or malposition which might occur in the reorga- 
nization of the exudative products which takes place in the first few 
days after operation. The value of the tube under such conditions 
is well illustrated in Case 5, in which the operation, which was anti- 
cipated to be of unusual difficulty, high risk, and dubious results, 
proved to be one of greatest simplicity, little danger, and complete 
success. It should be remembered that in the tube we have available 
a means of carrying the contents of the intestine through a point of 
actual, impending, or potential obstruction in the intestinal tract and 
that it can serve a most useful purpose in cases in which such danger is 
a possibility. 

The possibility that the tube may be of service in certain distur- 
bances in the neuromuscular mechanism of the intestinal tract is sug- 
gested by Case 6; although the immediate cause of the condition was 
not due to spasm, the primary cause may have been. During the past 
few years only have we gained any accurate knowledge of the neuro- 
muscular mechanism of the gastro-intestinal tract. The original 
investigations of Gaskell, and the later work of Keith and Cannon 
have resulted in establishing certain facts, the most important of which 
in the present connection concerns the presence in the gastro-intestinal 
tract of nodes or controlling sphincters. Variations in the functiona- 
ting of these sphincters cause disturbances in the section of the alimen- 
tary tract immediately under its control, with secondary disturbai ces 
in segments higher up. The extent to which such disturbances (that 
is, tonic spasm, atony due to sympathetic irritation, or irregular 
contractions due to parasympathetic irritation) may be responsible 
by reason of long continued action for actual disease in the gastro- 
intestinal tract and associated organs is yet to be determined. It is 
quite reasonable to believe; however, that abnormal functioning of 
such sphincters continued over a long period may, with the addition 
of other factors, result in disease processes which otherwise would not 
have occurred. 

One of the most interesting anomalies in the intestinal tract is 
congenital dilatation of the colon or Hirschsprung's disease. No 
satisfactory explanation of the condition has been advanced, but from 
the character of the dilatations which occasionally occur in other 
portions of the intestinal tract it seems that chronic spasm of the recto- 



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THE RUBBER TUBE IN INTESTINAL SURGERY . 161 

sigmoid sphincter is an important factor in the development of the 
condition. If this be true, it is possible that in certain cases of Hirsch- 
sprung's disease, some method may be divised for forcible and repeated 
stretching of the sphincter at the rectosigmoid juncture, by instru- 
mentation similar in principle to that so successfully used in cardio- 
spasm. Should such treatment be possible, a formidable operation 
could be avoided. 

Another point of interest to be mentioned in this connection is the 
suggestion which has been made by Sampson Handley in his article 
on ileus duplex. He believes that certain cases of postoperative intes- 
tinal paresis with general peritonitis are due to spasm not only of the 
long sphincter in the terminal and pelvic ileum, but also of the sphincter 
in the termination of the pelvic colon (or at the rectosigmoid juncture), 
and that the percentage of recoveries from operations in such cases 
will be much higher if both the distended and obstructed ileum and 
colon are drained than if an enterostomy only is done. He accomplishes 
this procedure by an ileocolic anastomosis (ileum to ascending colon) 
combined with a cecostomy. In this way he makes certain that in the 
33.33 per cent of cases in which both ileum and sigmoid are obstructed 
a safety valve is provided in the catheter colostomy. We have found 
that in some of these cases a tube introduced through the rectum 
could be passed beyond the point of spasm at the rectosigmoid, thereby 
avoiding the necessity of a colostomy. In certain cases of paresis, the 
anastomosis of ileum and colon, rather than enterostomy, should be 
given more consideration than has been afforded it in the past. 

The various conditions under which we have employed the tube 
frequently necessitate serious and difficult operations in which any 
factor which adds to the safety of the operation and to the prospects of 
a satisfactory result is most desirable. It has been our experience 
that in the rubber tube such a factor is available. 

BIBLIOGRAPHY 

1. Balfour. D. ('.: A method of anastomosis between sigmoid and rectum. Ann. 
Surg., 1910, li, 230-241. 

2. Cannon, W. B.: The mechanical factors of digestion. New York, Longmans, 
lfll. 227 pp. 

S. Gaskell, W. H. : On the structure, distribution and function of the nerves which 
ianervate the visceral and vascular systems. Jour. Physiol., 1885, vii, 1-80. 

4. Handley, W. S.: Ileus duplex (Inflammatory entero-colic ileus). Lancet, 1915, 
i, 900-906. 

'19-11 



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162 D. C. BALFOUR 

5. Keith, A.: An account of six specimens of the great bowel removed by operation: 
With some observations on the motor mechanism of the colon. Brit. Jour. Surg., 
1914-1915, ii, 576-599. 

6. Morison, J. R.: Intestinal obstruction. Lancet, 1911, i, 170S-1704. 

7. Mummery, P. L.: Diseases of the colon and their surgical treatment. New 
York, Wood. 1910. 322 pp. 



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UROGENITAL ORGANS 



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TOXICITY OF PYELOGRAPHIC MEDIUMS: REPORT 
OF A DEATH FOLLOWING THE USE OF THORIUM 

NITRATE* 

E. H. WELD 

There is no longer any question as to the value of pyelography. 
Whenever renal catheterization is necessary for diagnostic purposes 
the procedure is almost routine. Urologists have sought an opaque 
medium which would not be injurious, and all experimental work in 
the past has been done with the view of determining the effect of 
pyelographic mediums on the kidney tissue. It has been shown 
definitely that colloidal silver solutions are injurious to the kidney 
tissue and that they get into the circulation. I have recently shown 
that all pyelographic mediums and various dyes are rapidly absorbed 
from the kidney pelvis. The striking clinical results that are often 
obtained in cases of pyelonephritis by pelvic lavage with silver nitrate 
solutions have been explained as due to the action of the silver solution 
not only by its local effect on the kidney pelvis but also by its permea- 
tion of the kidney tubules (Braasch). In view of the work we have 
done in demonstrating that substances are absorbed from the tubules 
of the medullary portion, it seems plausible that such an explanation 
of the action of silver nitrate is correct. A recent death following 
pyelography for which a solution of thorium nitrate was used led us 
to make a study of the toxicity of the different pyelographic mediums. 

Report of a Case 

Case 64235. A woman, aged 55, who was examined at the Mayo 

Clinic, Feb. 27, 1919, died following a urethral catheterization in which 

thorium nitrate was used as the pyelographic medium. The patient 

first came to the clinic in February, 1912, at which time she complained 

of pain with epigastric distress, rather typical of gallbladder disease. 

A cholecystostomy was performed and a chronic catarrhal cholecystitis 

* Reprinted from Jour. Urol., 1919, iii, 415-426. 
165 



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166 E. H. WELD 

(strawberry gallbladder) with a large number of stones was found. 
Recovery was uneventful and the patient was in good health until three 
months before her last examination; she then began to have attacks 
of epigastric distress coming on at night every two weeks, a dull 
severe ache with a sensation of fullness at the right costal border 
which would last two or three hours. She complained of some indefi- 
nite urinary symptoms. The examination of the urine showed it 
to be practically normal. The hemoglobin was 77 per cent; x-ray 
examination of kidneys, ureters, and bladder was negative. 

The patient was given a cystoscopic examination in order to 
identify the source of the abdominal pain. A slight irritability of the 
bladder with a few areas of chronic inflammation, particularly at the 
right and left base of the bladder, was noted. Both ureters 
were of normal length and the secretion was clear. A specimen showed 
a moderate number of red blood cells. A differential functional test 
showed 17 per cent on the right and 12 per cent on the left with a 
return flow from the bladder of 2 per cent. Because of the right- 
sided pain, a pyelogram was made. Thorium nitrate, prepared by a 
well known pharmaceutical company, was the opaque medium used 
and was carefully injected. The patient did not complain of pain, 
she was somewhat weak and faint for a short time after getting off 
the table, but was able to go to her hotel. At the end of six hours 
she was suddenly seized with nausea, vertigo, and weakness. The 
symptoms became rapidly worse, with pronounced vomiting, and 
prostration, and she died at 7 p. m., nine hours after the pyelogram was 
made. The clinical diagnosis was negative so far as a pathologic 
condition in the kidney was concerned. The nature of her death 
suggested acute toxemia, evidently the result of pyelography. 

At necropsy marked general arterial sclerosis, moderate fibrosis, 
fatty myocarditis, arteriosclerotic atrophy of the kidney, slight 
traumatic( ?) hemorrhage in the pelvis of the right kidney, slight cathe- 
terization bruising of the urethra and ureteral mouths, marked edema 
of both lungs, small hypernephroma of the right adrenal gland about 
2 cm. in diameter, right apical fibrous adhesive pleuritis, old atrophic 
cholecystostomy scar of the abdomen, moderate arteriosclerotic 
deformity of the gallbladder, fibrous adhesions between the gallbladder, 
parietal peritoneum, hepatic flexure of the colon, first portion of the 
duodenum, and the under surface of the liver, marked parenchymatous 
fatty changes in the liver, slight hyperplasia of the spleen, and petech- 



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TOXICITY OF PYELOGRAPHY MEDIUMS 167 

ial hemorrhages in the mucous lining of the greater antrum of the 
stomach were found. Microscopic examination of the kidney showed 
some cloudiness of the tubular epithelium, with areas of acute 
congestion. 

The stock of thorium nitrate solution on hand at the time was at 
once sent to the manufacturer, but unfortunately none was saved to 
be tested physiologically in our own laboratories. Several specimens 
of thorium nitrate solution of different ages were tested, however, 
and these showed varying toxicity. 

Physiologic Tests of the Toxicity of the Mediums 

Dogs were anesthetized and kept under light constant ether tension 
by the Connell apparatus. The carotid artery was arranged to record 
carotid blood pressure (mercury manometer). The femoral vein 
was exposed so that injections could be made easily either by syringe 
or burette. A 25 per cent solution of sodium bromid, a 25 per cent 
solution of potassium iodid, a 25 per cent solution of sodium iodid, 
and a 15 per cent solution of thorium nitrate were tested. The 
intravenous injection of sodium bromid in four different dogs produced 
practically no effect, even when 55 c.c. were given. Usually there was 
a slight increase in blood pressure, possibly due to an increase in the 
fluid volume. The injection of 2 or 3 c.c. of a 25 per cent solution 
potassium iodid caused the blood pressure to drop to zero, and almost 
instant death. When 50 c.c. of a 25 per cent solution of sodium iodid 
were used in two experiments, a very slight reaction followed from 
which the animal soon recovered. The toxicity of the 15 per cent 
solutions of thorium nitrate seemed to vary with the different ages of 
the solutions. Twenty-two cubic centimeters from Bottle A caused 
the death of the animal. Ten cubic centimeters from Bottle B caused 
a decided reaction noted in the blood pressure curve. One hundred 
cubic centimeters from Bottle C produced no apparent reaction. 
Fifty cubic centimeters from Bottle D caused the death of the animal. 
Forty cubic centimeters from Bottle E caused death, as did also 25 
c.c. from Bottle E, when the solution was given to a slightly smaller 
animal. The contents of Bottle A was approximately one year old, of 
Bottle B approximately two months; Bottles C, D and E had just been 
received from the manufacturers. 

Potassium iodid should be used with great care as a pyelographic 



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168 E. H. WELD 

medium because of its toxicity and because of the fact that it is readily 
absorbed from the kidney pel v is. Death following the use of potassium 
iodid is very evidently due to the potassium radicle, since sodium 
iodid produces very little effect. 

At least one of the toxic effects of thorium nitrate is on the heart 
muscle, as may be shown by the fact that cardiac failure follows the 
administration of thorium nitrate even after section of the vagi and 
the administration of such drugs as nicotin and atropin. Thorium 
nitrate seems to vary in toxicity according to the age of the solution, 
possibly because of the conditions under which it is kept. 

Unfortunately, sodium or potassium iodid, in a solution of 20 to 25 
per cent as originally recommended, * often causes considerable local 
irritation when used in the renal pelvis and bladder in man. 

Sodium bromid is non-toxic, cheap, easily prepared, readily ac- 
cessible, non-irritating, and would seem to be the best medium yet 
brought forward. We advise a 20 per cent solution for pyelography; 
a 10 or 15 per cent solution is sufficient for cystography. The drug 
should be chemically pure, and the solution should be sterilized by 
boiling before it is used. 

PROTOCOLS 

Experiment 300, Dog D124, April 22, 1919. A dog weighing 5 kg. 
was prepared in the usual manner. In one and-one-fourth minutes 
1 c.c. of a 25 per cent solution of sodium bromid was injected into the 
right femoral vein; the pulse rate remained practically unaffected 
but the blood pressure was raised about 3 mm. 

After allowing forty -five minutes for the dog to recover, 1 c.c. of a 
25 per cent solution of potassium iodid was injected in one and one- 
fourth minutes. A decided reaction, probably toxic, followed. 

The dog was allowed forty-five minutes in which to recover and 
1 c.c. of a 15 per cent solution of thorium nitrate was injected which 
caused a slight irregular pulse curve. The solution, approximately 
one year old, came from Bottle A. 

After eighteen minutes, 5 c.c. of thorium nitrate were injected in 
two and one-half minutes; this caused a rise in blood pressure of 
about 30 mm., which gradually decreased for three minutes, and then 
the blood pressure seemed to remain normal. The solution came 
from Bottle A. 

Again after eighteen minutes 5 c.c. of a 25 per cent solution of 



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TOXICITY OF PYELOGRAPHY MEDIUMS 



169 



sodium bromid were injected which caused a very slight rise of blood 
pressure, and after another eighteen minutes 2 c.c. of a 25 per cent 
solution of potassium iodid were injected into the femoral vein. This 
caused a rapid fall in blood pressure and the death of the animal. 





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Experiment 306, Dog D106, April 22, 1919. A dog weighing 4.5 
kg. was injected with 10 c.c. of a 25 per cent solution of potassium 
iodid into the right femoral vein at the rate of 2 c.c. a minute. The 



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170 



E. H. WELD 



blood pressure rose 6 mm. and the pulse curve was increased slightly 
in amplitude. After the completion of the injection the blood pressure 
returned to normal. 



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The animal was allowed forty-five minutes in which to recover when 
10 c.c. of thorium nitiate were injected at the rate of 2 c.c. a minute. 
This gave a decided toxic curve and a slight rise in blood pressure, 
after which the curve returned to normal. The solution, approxi- 
mately two months old, was taken from Bottle B. 



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TOXICITY OF PYELOGRAPHY MEDIUMS 171 

After fifteen minutes the injection of 2.5 c.c. of a 25 per cent solu- 
tion of potassium iodid at the rate of 2 c.c. a minute caused the imme- 
diate death of the animal (Figs. 92 and 93). 

Experiment 311, Dog D131, April 23, 1919. A dog weighing 4.9 
kg. was injected with a 15 per cent solution of thorium nitrate allowed 
to flow by gravity from a burette into the right femoral vein. For 
the first three minutes the rate was 1 c.c. a minute; 5 c.c. had entered 
in four minutes, 8 c.c. in six minutes, 10 c.c. in eight minutes, 16 c.c. 
in nine minutes, 20 c.c. in ten minutes, 22 c.c. in eleven minutes, 
at which time the animal died. It is probable that the animal would 
have died if a smaller quantity had been used. The solution, approxi- 
mately one year old, came from Bottle A (Fig. 94). 

Experiment 312, Dog D132, April 23, 1919. A dog weighing 4.7 
kg. was injected with a 25 per cent solution of sodium bromid allowed 
to flow slowly from a burette into the right femoral vein at the rates 
noted in the preceding experiment. Thirty cubic centimeters were 
injected in thirteen minutes without causing any marked reaction. 
The blood pressure rose slightly, and the pulse seemed to increase in 
volume. The animal was allowed to remain on the table thirty 
minutes, and another record was taken (Fig. 95). 

Experiment 314, Dog C268, April 24, 1919. A dog weighing 12 kg. 
was injected with a 15 per cent solution of thorium nitrate, allowed 
to flow gradually from a burette into the left femoral vein. Six cubic 
.centimeters had entered in five minutes, 10 c.c. in eight minutes, 30 
c.c. in thirteen minutes, 50 c.c. in eighteen and one-half minutes. 
Following this the animal was given one hour in which to recover when 
50 c.c. more were allowed to flow into the vein in thirteen minutes. 
This injection did not seem to have any toxic effect on the dog. The 
solution, approximately one month old, came from Bottle C which had 
recently been received from the manufacturer. 

Experiment 316, Dog D135, April 28, 1919. A dog weighing 7.2 
kg. was injected with a 25 per cent solution of sodium bromid allowed 
to run by gravity from a burette into the left femoral vein at the rate 
of 3 c.c. in three minutes, 6 c.c. in eight minutes, and 55 c.c. in eleven 
minutes. This produced no ill effect. There was a slight rise in blood 
pressure which gradually returned to normal after the injection had 
been discontinued. The animal was killed by injecting 2.5 c.c. of 
15 per cent colloidal silver solution directly into the vein. 

Experiment 317, Dog D136, April 28, 1919. A dog weighing 10.4 



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B. H. WELD 



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TOXICITY OF PYELOGRAPHY MEDIUMS 173 

kg. was injected with thorium nitrate allowed to run by gravity from a 
burette into the left femoral vein. In the first minute 6 c.c. were 
injected, causing a rapid fall in blood pressure. The animal was 
allowed one minute in which to recover. At the end of three minutes 
9 c.c. had been injected, in four minutes 12 c.c, in five minutes 14 c.c, 
in six minutes 17 c.c, in seven minutes 21 c.c, in eight minutes 32 c.c, 
in nine minutes 37 c.c, in ten minutes 41 c.c, in eleven minutes 44 c.c, 
in twelve minutes 47 c.c, in thirteen minutes 50 c.c The solution was 
then injected at the approximate rate of 4 c.c a minute. At the end 
of eight minutes the blood pressure gradually began to drop, and 
continued to fall until 50 c.c had been injected when the animal died. 
The solution was taken from a bottle (Bottle D) which had been 
received from the manufacturer about one week before. The bottle 
had not been opened until it was used in this experiment (Fig. 96). 

Experiment 319, Dog D138, April 29, 1919. A dog weighing 
9 kg. was injected with thorium nitrate solution allowed to flow from 




Fio. 97. — Death following the injection of 40 c.c. of thorium nitrate solution(Experiment 

(319, Dog D138). 

a burette into the left femoral vein. In one minute 4 c.c. were injected, 
in two minutes 10 c.c, in three minutes 15 c.c, in four minutes 20 c.c, 
in five minutes 25 c.c, in six minutes 30 c.c, in seven minutes 34 c.c, 
in eight minutes 38 c.c, in eight and one-half minutes 40 c.c, at which 
time the animal died. The blood pressure had risen gradually until 
SO c.c. had been given, and then it began to sink in a more rapid curve 
than that in which it had risen until death ensued three minutes later. 
The solution, which had not been used until this experiment, was 
taken from Bottle E (Fig. 97). 

Experiment 321, Dog D140, April 30, 1919. A dog weighing 
5.2 kg. was injected from a burette arranged to allow a 25 per cent 



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174 



E. H. WELD 



solution of sodium iodid to flow into the right femoral vein. In one 
minute 3 c.c. were injected, in two minutes 6 c.c, in three minutes 
9 c.c, in four minutes 13 c.c, in five minutes 17 c.c, in six minutes 
20 c.c, in eight minutes 25 c.c, in nine minutes 30 c.c. The curve 
was somewhat irregular at this time due to very light anesthesia. In 
ten minutes 33 c.c were injected, in eleven minutes 40 c.c. The 
animal struggled somewhat, due to light anesthesia. In thirteen 
minutes 44 c.c. were injected, in fourteen minutes 50 c.c There was 
apparently very little toxic effect. The animal was given 2 c.c. 
potassium iodid which caused instant death, apparently from heart 
failure. 

Experiment 327, Dog D141, May 1, 1919. A dog weighing 5.4 
kg. was injected with a 25 per cent solution of sodium iodid allowed to 
flow from a burette into the right femoral vein. In one minute 1.5 c.c. 
were injected, in two minutes 4.5 c.c, in three minutes 8 c.c, in four 




Fig. 98. — The injection of 50 c.c. of a 25 per cent solution of sodium iodid (Experiment 

327, Dog D141). 

minutes 11 c.c, in five minutes 16 c.c At this time there was a slight 
fall in blood pressure because of the too rapid injection. In six 
minutes 21 c.c. were injected, in seven minutes 24 c.c, in eight minutes 
31 c.c. The blood pressure fell again because of too rapid injection. 
In nine minutes 35 c.c. were injected, in ten minutes 43 c.c, in eleven 
minutes 50 c.c. The record was stopped; after fifteen minutes it was 
run for a short interval showing that the blood pressure had risen 
about 20 mm. above the original. From this experiment it would 
seem that sodium iodid is non-toxic, but when given rapidly intraven- 
ously causes a slight reaction (Fig. 98). 

Experiment 335, Dog D144, May 6, 1919. A dog weighing 5.8 
kg. with blood pressure of 150 mm. was injected with 15 c.c of a 
15 per cent thorium nitrate solution taken from Bottle E and 



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TOXICITY OF PYELOGRAPHY MEDIUMS 



175 



allowed to flow from a burette into the femoral vein at the rate 
of 3 c.c. a minute. The blood pressure gradually rose until it reached 
£00 mm. at the end of five minutes when it began to fall slightly; the 




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injection was, therefore, discontinued. The pulse became very slow 
and full, increasing to a large pulse pressure after the injection was 
stopped. The blood pressure in the meantime rose to 230 mm. 
Two minutes after the injection was stopped the blood pressure 
gradually began to fall and at the end of forty-five minutes it had 
dropped to 110 mm.; at this time Record 2 was taken. Ten cubic 
centimeters of a 15 per cent solution thorium nitrate were then injected 
in one and one-fourth minutes. This caused a rapid rise in blood 
pressure up to 165 mm. in one minute. The blood pressure began 
to fall, the heart became very slow, but recovered and the record was 
continued for twenty minutes and showed the gradual fall of the 
blood pressure, while the pulse pressure was large and the pulse very 
slow and full. As it was evident at the end of twenty minutes that 
the animal would die, the vagi were sectioned. This had no effect 
on the pulse or blood pressure, proving that the toxic effect was not 
on the central nervous system (Record 3, Signal C). Nicotin in- 
jected intravenously produced no effect; this showed that the effect 
of the drug was not on the nerve ganglion. Atropin was injected and 
produced no effect, demonstrating that the action was not on the 
nerve endings. The animal would probably have been killed at the 
first injection if more than 15 c.c. had been given. The action of the 
drug is directly on the heart, particularly when a large dose is given 
rapidly (Fig. 99). 

Physiologic Tests of the Toxicity of Pyelography Mediums 



25 per cent sodium 

bronrid j 

ta£ntl Amount Kcactionj 



Bottle 



15 per cent tho- 25 per cent potaa- I 25 per cent sodium 
rium nitrate i sium iodid iodid 



Amount 1 Reaction 



A mount Reaction • Amount Reaction 



300 
300 
306 
311 
312 
314 
316 
317 
310 
321 
327 
335 



1 c.c. 

5 c.c. 

10 c.c. 


None 
None 
None 


30 c.c. 


None 



55 c.c. None 



A 


1 c.c. 


None 


A 


5 c.c. 


Slight 


B 


10 c.c. 


Toxic 


A 


22 c.c. 


Death 


c 


100 c.c. 


None 


D 


50 c.c. 


Death 


E 


40 c.c. 


Death 



1 c.c. j Toxic 

2 c.c. i Death 
2 Hc.c. I Death 



25 c.c. | Death 

I 



50 c.c. I None 
50 c.c. I Very slight 



I 



BIBLIOGRAPHY 

1. Cameron, D. F.: Aqueous solutions of potassium and sodium iodids as opaque 
mediums in roentgenography. Preliminary report. Jour. Am. Med. Assn., 1918, Ixx, 
754-755. 



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THE PELVIS OF THE KIDNEY AS A POSSIBLE SOURCE 

FOR INFECTION OF THE BLOOD STREAM: A 

PRELIMINARY REPORT* 

J. A. H. MAGOUN, JR. 



During recent years it has been generally conceded that in cases of 
renal infection the kidney is infected secondarily following a primary 
bacteremia. In some instances it seems that the kidney, previously 
infected either through the blood stream or by an ascending infection, 
may be the cause from which a bacteremia results. For the purpose 
of investigating this interesting problem, experiments have been con- 
ducted under the direction of the Departments of Urology, of Experi- 
mental Bacteriology, and of Experimental Surgery, with reference 
to the following questions: 

1. Can organisms pass from the pelvis of the kidney into the blood 
stream? 

2. Are the conditions under which they pass at all analogous to the 
pathologic status found clinically? 

3. Are there clinical cases in which the kidney has acted as a focus 
of infection? 

Our investigations have been concerned, as yet, only with the first 
two of these hypothetic questions. 

The literature concerning the absorption from or the passage of 
organisms through the kidney is very meager. Albarran was the 
first to investigate experimentally the infections of the blood stream 
through the kidney. In 1888, working with the Bacillus pyogenes, 
which was afterwards identified as the Bacillus coli by Krogius, 
Achard and Renault, he produced infection in the blood stream by 
introducing the organism into the ureter. His work was without 
previous bacteriologic control of the blood, however, and in many 
cases peritonitis occurred. He traced the organism from the bladder to 

* Reprinted from Jour. Am. Med. Assn., 1920, Ixxiv, 73-75. 
1^-12 177 



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178 J. A. H. MAGOUN, JR. 

foci of infection in the kidney; "from these foci the organisms go into 
the connective tissue and then penetrate into the blood vessels, enter 
the circulation, and lead to far off emboli." Thus it is seen that 
thirty years ago the thought was suggested that the kidney might be a 
focus for blood stream infection. 

Burns and Schwartz do not believe that absorption takes place from 
the pelvis of the kidney under normal conditions. If an acute pyelitis 
occurs, however, absorption and the clinical phenomena of chills 
and fever result. These authors consider such clinical manifestations 
due to the absorption of urine and bacterial toxin either from the 
blood vessels or lymphatics of the renal pelvic mucosa directly, or 
from the urine and bacterial toxins retained in the uriniferous tubules. 
They do not suggest, however, that these clinical symptoms may be 
due to the passage of the bacteria through the kidney into the blood 
stream, thus causing a bacteremia. In their later work, after the 
injection, by the gravity or syringe method, of indigo carmin and india 
ink particles into the previously ligated ureter, they found these 
substances in the opposite kidney, in the liver, lungs, and spleen. 
They then conclude: "It is reasonable to suppose that if particles of 
ink can travel in this manner, bacteria and other foreign substances 
can do likewise." 

Macht states that certain drugs or poisons may be absorbed 
through the walls of the ureter and the kidney pelvis. Weld has shown 
with what ease certain drugs may be absorbed from the renal pelvis, 
and the untoward action of some of them. Weld's finding that 
"absorption from the kidney pelvis indicates that the kidney may 
be a focus of infection which should always be considered," stimulated 
me to make the present investigation. 

EXPERIMENTAL WORK 

Dogs were used in all the experiments. The animals were etherized 
with a constant ether tension; their condition was kept as near normal 
as possible by the judicious use of heat, and so forth. In some of the 
experiments the blood pressure was recorded. All operative manipu- 
lations were carried out with the minimum of trauma and hemor- 
rhage. Bacillus prodigiosus was the organism chosen since it is easily 
identified, since it probably never occurs spontaneously in the sites 
cultured, and since it is rarely the cause of bacterial contamination 



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THE PELVIS OF THE KIDNEY 179 

in the laboratory. The bacillus was grown in broth cultures and in- 
jected by the gravity method. 

A straight glass tube about 2.5 mm. in diameter was connected by a 
T-tube to a cannula inserted into the ureter and to a graduated burette. 
The straight glass tube was graduated in cubic millimeters. A stop 
cock was inserted on each side of the T-tube. The fluid containing 
the bacteria was placed in the burette and allowed to flow into the 
graduated tube to any desired height. At this definite, and controlled 
pressure it was then allowed to enter the ureter. Great care was taken 
to exclude air from the entire system and not to contaminate adjacent 
tissues. 

The dogs were killed with ether at the end of from two to three hours 
and cultures taken -from the heart's blood, the lungs, liver, spleen, 
inferior vena cava opposite the renal vein, right kidney cortex and 
medulla, and left kidney cortex and medulla. The cultures were 
made by planting from 2 c.c. to 5 c.c. of blood and from 0.2 c.c. to 
0.5 c.c. of the tissue juice of the various organs into tall tubes of glucose 
broth. The material from the tissues was obtained by aspirating the 
macerated particles and juice into sterile pipettes. The inoculated 
tubes were allowed to stand at room temperature for from forty-eight 
to ninety-six hours. The positive cultures were then plated on plain 
agar. 

Series 1. — In the first series through a lumbar incision a cannula 
was inserted into the left ureter from 2 cm. to 4 cm. from the pelvis 
of the kidney. A twenty-four hour broth culture of Bacillus prodi- 
gio*us was then permitted to flow into the pelvis at from 10 cm. to 
30 cm. pressure. From two to three hours afterward the dogs were 
killed with ether and cultures made as outlined above. Results are 
shown in Table 1. In 12 experiments even with this low pressure 
Bacillus prodigiosus was recovered from the blood stream or other 
organs in three instances. It was found in the left kidney in all but 
two of the experiments. 

Series 2. — The procedure in the second series was the same as in the 
first, with the exception that the pressure at which the organisms were 
passed into the ureter was increased to from 60 cm. to 78 cm. Results 
are shown in Table 2. At this pressure, which was slightly less than 
the secretory pressure of the kidney, the organisms were recovered 
from the blood stream or other organs in six of seven experiments, and 
they were recovered from the left kidney in all. 



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180 



J. A. H. MAGOUN, JR. 



Series 3. — In the third series in addition to the procedure followed 
in Series 1 and 2 a cannula was inserted into the right ureter 4 cm. 
above the bladder; to the cannula was attached a straight glass tube. 
The cannula inserted into the left ureter was also 4 cm. above the 
bladder. A forty-eight hour broth culture of Bacillus prodigiosu* 
and washings from forty-eight hour agar slants were placed in the 
burette and allowed to flow into the left ureter, while the pressure was 
kept under 21 cm. The tubing connected with the cannula in the left 
ureter was then clamped. The femoral vein was isolated and from 
100 c.c. to 150 c.c. of a 5 per cent sodium sulphate solution were in- 
jected slowly. The secretory pressure of the right kidney was meas- 
ured in the graduated tube connected with the right ureter. After 
two to three hours the routine procedure as previously described was 
carried out. The organisms were introduced under a very low pressure 
and the intrapelvic pressure was subsequently increased by stimulation 
of the kidney. The results are shown in Table 3. In four of these 
five experiments Bacillus prodigiosus was recovered in other organs 
than the kidney. 

It may be concluded, therefore, that bacteria can pass from the 
kidney pelvis into the blood stream and that they may do this under 
conditions analogous to some of the pathologic states found in man. 



Table 1.— R 


ESULTS OF EXPERIM 


ents in Series 1 




Pressure above kid- 
ney pelvis 
cm. of water 


Positive cultures 


Experiment 


Bacillus prodioiotui 


550-19 


20 to 30 


1. Renal vein 

2. Left kidney cortex 

3. Left kidney medulla 


560-19 


20 to 30 


1. Left kidney medulla 


562-19 


20 to 30 


1. Left kidney cortex 

2. Left kidney medulla 


565-19 


10 to 30 


1. Heart blood 

2. Liver 

3. Renal vein A and B 


592-19 


20 to 30 


All cultures negative 


618-19 


20 to 30 


1. Left kidney cortex 


620-19 


20 to 30 


1. Left kidney cortex 


630-19 


20 to 30 


1. Left kidney cortex 

2. Right kidney cortex 


649-19 


20 to 30 


1. Left kidney cortex 


654-19 


20 to 30 


1. Left kidney cortex 


657-19 


20 to 30 


1. Left kidney cortex 


666-19 


20 to SO 


All cultures negative 



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THE PELVIS OF THE KIDNEY 



181 



Table 2. — Results of Experiments in Series 2 



i 



Experiment 
531-19 

554-19 



704-19 



800-19 
801-19 

802-19 
803-19 



Pressure above kid- 
ney pelvis 
cm. of water 

78 



70 



60 



60 
60 

60 

78 



Positive cultures 
Bacillus prodigiosua 

1 . Left kidney cortex 

2. Left kidney medulla 

1. Heart blood 

2. Right kidney 

3. Liver 

4. Renal vein? 

1. Lung 

2. Renal vein A and B 

3. Heart blood A and C 

4. Right kidney cortex 

5. Left kidney cortex 

6. Right kidney medulla 

7. Liver A and B 

8. Spleen 

1. Renal vein 

2. Left kidney cortex 

1. Liver A and B 

2. Renal vein A, B, and C 

3. Heart blood A, B, and C 

4. Spleen 

5. Right kidney cortex 

1. Liver A and B 

2. Spleen 

1. Heart blood A, B, and C 

2. Renal vein 1 and 2 

3. Liver 1 and 2 

4. Left kidney cortex 



Table 3. — Results of Experiments in Series 3 



Experiment 
739-19 



Pressure in 
left ureter 
cm. of water 

20 



756-19 

760-19 
804-19 
805-19 



20 

20 
20 
20 



Pressure in 
right ureter 
cm. of water 

65 



Positive cultures 
Bacillus prodigioius 

1. Lung 

2. Heart blood A, B, and C 

3. Renal vein A and B 

4. Liver 

5. Right kidney cortex 

6. Left kidney cortex 

64 1. Renal vein 

2. Liver 

3. Left kidney cortex 
78 1. Liver 

2. Left kidney cortex 

50 1. Heart blood 

2. Left kidney cortex 

65 All cultures negative 



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18£ J. A. H. MAGOUN, JR. 



BIBLIOGRAPHY 



1. Albarran, J.: fitude sur le rein des urinaires. These de Paris, Steinheil, 1889. 

2. Burns, J., and Swartz, £.: Absorption from the renal pelvis in hydronephrosis 
due to permanent and complete occlusion of the ureters. Jour. Urol., 1918, ii, 445-455. 

3. Krogius, Achard and Renault: Quoted by Brown, T. R.: The bacteriology of 
cystitis, pyelitis and pyelonephritis in women, with a consideration of the accessory 
etiological factors in these conditions, and of the various chemical and microscopical 
questions involved. Johns Hopkins Hosp. Reports, 1902, x, 11-89. 

4. Macht, D. I.: Concerning the absorption of drugs and poisons from the ureter 
and pelvis of the kidney. Jour. Urol., 1918, ii, 481-485. 

5. Weld, E. H. : Renal absorption with particular reference to pyelography mediums. 
Med. Clin. North Am., 1919, iii, 712-781. 



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HEMATOGENOUS INFECTIONS OF THE KIDNEY* 

W. J. MAYO 



The surgical aspects of nephritis have led to extensive discussion, 
and but little agreement exists with regard to the types that are not 
clearly surgical. Wide differences of opinion are also manifest among 
those who have given the most time and attention to the study of 
nephritis in general. The accumulated literature on the subject is 
monumental; much of it, unfortunately, is confusing, and often even 
the fundamentals are the subject of controversy. Recently, however, 
articles have been published that help to clear up some of the moot 
questions. 

Historically, the chief point of interest with reference to nephritis 
is the profound knowledge of the various phases of the disease exhibited 
by Richard Bright, one of a long line of brilliant workers in Guy's 
Hospital, London. In 1827 and again in 1836 Bright, in epoch 
marking papers on edema and on albuminuria, pointed out that 
fundamentally there are two kinds of nephritis: Type 1, the acute 
or "wet " nephritis; and Type 2, the chronic or " dry " nephritis. 

Type 1, which involves the kidney filter, was to be recognized 
pathologically in cases in which the large white kidney was found. 
Clinically, the type was characterized by edema, especially in the 
acute stage, and by urine containing albumin and casts, and at 
times blood corpuscles, the urinary findings varying in extent with the 
acuteness of the process and the amount of involvement of the kidneys. 
Both kidneys are always involved and exhibit a wide pathologic 
architecture. The morphology varies as the toxic agents vary in 
toxicity and affect different structures of the kidney. 

Bright* s Type 1 nephritis. — Since the publication of Bright's work, 
we have learned that Type 1, or the " wet " type of nephritis, is usually 
the result of toxins developed in the course of infectious diseases. 

* Presented before the Section on Urology at the Seventieth Annual Session of the 
American Medical Association, Atlantic City, June, 1919. 

Reprinted from Jour. Am. Med. Assn., 1919, Ixxiii, 1023-1026. 

183 



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184 W. J. MAYO 

Diphtheria antitoxin affords the best known example of the effect of 
bacterial toxins on the kidney; it may produce changes in the kidney 
analogous to the nephritis which sometimes develops in cases of 
diphtheria. The frequency with which Bright's Type 1 and infective 
nephritis follow lesions of the skin and mucous membrane, especially 
in children, is worthy of note, as shown by the nephritides following 
scarlet fever, tonsilitis and so forth. In the adult, exposure to cold, 
especially of the cutaneous surfaces, plays a definite r61e. The value 
of the skin as an aid to elimination in cases of defective kidney function 
has long been well known. The effect produced by hot packs and 
similar therapeutic measures is to cause a flow of perspiration which 
may eliminate large amounts of chlorids and some urea. 

It is true that acute nephritis may be produced by other toxic agents, 
such as cantharides, but to all intents and purposes an infection lies 
behind it. The edema is to a large extent due to a failure of elimina- 
tion of chlorids. Chlorids, usually taken in the form of common salt, 
are a constant requirement of all an : mal life. The herbivorous and 
omnivorous animals obtain the necessary amount in the form of salt, 
while the carnivorous obtain a sufficient amount from the flesh which 
they consume. The chlorids are largely excreted by the kidneys. In 
acute nephritis, chlorid is not fully eliminated, and edema results. 
The physical and chemical reactions involved in the production of 
edema by chlorid retention are still greatly disputed, however, and 
it is apparent that varying factors are to be considered. 

Bright's Type 2 nephritis. — Bright's Type 2, called the dry type 
because edema is not present, involves the connective tissue and blood 
vessels, especially the arteries; the patient suffers from headache, 
nausea, vomiting, hypertension, and other symptoms of uremia. 
The symptoms may be latent for long periods. Urea retention is one 
of the final consequences of this type. While urea will not of itself, 
when in excess in the blood, produce uremia, it is closely associated 
with if not one of the agents which produce the uremic manifestations. 
Both kidneys are involved, and pathologically in the typical case the 
kidneys are contracted and granular. The urine is of low specific 
gravity, pale, and large in amount. The urinary findings may consist 
only of an occasional cast and a trace of albumin, although at times 
there may be large amounts of albumin. This type of Bright's 
disease is closely associated with or is a part of a general vascular 
disease, and perhaps should not be described as a true primary nephri- 



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HEMATOGENOUS INFECTIONS OF THE KIDNEY 185 

tis. Changes in the heart are so characteristic of chronic Bright's 
disease that the appellation of cardiorenal disease is at times not 
inappropriate. The pathologic architecture varies with the situation 
of the chief connective tissue deposits and the changes in the renal 
vascular system. Bissell and other pathologists call attention to the 
fact that many of the changes in the kidney called nephritis are regres- 
sive in character. Neither infections nor the products of infection, 
so far as is known, play an important part in the etiology of Bright's 
Type 2. The cause of the condition is as yet unknown, but it is 
probably due to disorders of metabolism. 

Edema may develop in chronic Bright's disease (Type 2), but if it 
does it is almost invariably the result of cardiac failure and not of 
salt retention. Widal had divided nephritis functionally into two 
forms: the chloremic or salt retention type, corresponding to Bright's 
Type 1, and the azotemic, nitrogen, or urea retention type, correspond- 
ing to Bright's Type 2. It has been asserted by various authorities 
that chronic Bright's Type 2 is the late result of Type 1. I am con- 
vinced, however, that Bright's Types 1 and 2 are entirely independent 
diseases. 

A discussion of the differentiation is unnecessary here, but the 
confusion seems to arise from mixed types. In certain varieties of 
Bright's 1VP e 1> chronicity may be a feature. This is especially true 
of a form of Type 1, caused by chronic focal infections. I have seen 
what were believed to be cases of Bright's Type 1, caused by chronic 
infections of the teeth, tonsils, gallbladder, or by duodenal ulcer, and 
so forth. The patients recovered from the nephritic disturbance after 
operative cure of the focus of infection. Subacute infections, with 
slowly sterilizing abscesses, often cause symptoms of a nephritis which 
disappears as the cause is removed. Excessive connective tissue may 
develop in the kidneys in some cases of Type 1 so that they closely 
resemble the contracted kidneys of Type 2; but the vascular changes 
are different. Again, chronic Bright's disease, Type 2, acts as a cause 
for lowered resistance of the kidneys, and a secondary true nephritis 
of Type 1 may be added to the condition, especially as a terminal 
infection leading to the frequent postmortem finding of death from 
acute nephritis superimposed on chronic nephritis. This confusion 
is further increased in some cases by pathologic changes in the kidney, 
the late results of unrecognized hematogenous infection which might 
well be called Type 3. 



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186 W. J. MAYO 

Function of the kidney. — Rowntree calls attention to the fact 
that medicine of the last decade centers around the question of func- 
tion, so far as the kidney is concerned. The capacity of the kidney to 
carry on its work, rather than its appearance, has come to be recognized 
as the important factor. This is well shown by the value clinically 
of the phenolsulphonephthalein test and the test of the chemistry of 
the blood. The percentage of urea in the blood or the phenolsulpho- 
nephthalein test will frequently give a clue to the state of the kidneys 
that cannot be obtained from the urinary findings. 

That the kidney in health filters bacteria out of the blood, and 
by so doing receives no injury, is a fact too well known to require 
comment. It is the retention of the bacteria in the kidney which 
produces the trouble. But we know much less about its ability to 
filter out toxic materials. In the greater number of cases of nephritis 
no bacteria are found, and we must believe that it is some material, 
the result of infection, rather than the bacteria themselves that cause 
the trouble, although it is possible that an ultramicroscopic organism 
exists as the causative factor. The kindey normally filters out urea, 
which is the ash of protein derivatives, the amino-acids. The patient 
with a granular, contracted kidney (Bright's Type 2) must of necessity 
pass a large quantity of urine; the specific gravity is low because the 
kidney filter is damaged and fails to eliminate normal concentrations 
of urea and similar bodies. As these products are not threshold 
bodies, they are always to be found in both the blood and the urine. 

On the contrary, sugar in the blood is a threshold body. When it 
rises beyond the normal, the excess flows off through the urine, and 
diabetes results. The threshold, however, is not an exact point, and 
many persons with crops of boils or carbuncles may, by testing the 
blood for sugar percentages, be shown to have an increased amount 
of blood sugar without having sugar in the urine, just as in others a 
low threshold permits the escape of sugar from slight temporary 
causes, so-called dietetic or alimentary glycosuria, which is without 
pathologic significance. 

Embryologically, the kidney has a double origin: First, the ureter, 
pelvis, calices, and straight collecting tubules, all lined with pavement 
epithelium, which are derived from the wolffian duct and have no 
function beyond that of collecting urine as it is formed. The chief 
response of the part of the kidney thus derived, when diseased, con- 
sists in the development of infections, calculi, and so forth, and if 



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HEMATOGENOUS INFECTIONS OF THE KIDNEY 187 

the disease is a malignant, it is a true carcinoma. Obstructions 
to the urinary outflow at any poiqt are most potential of mischief 
through failure of drainage. The medullary part of the kidney is 
composed of the urinary collecting channels just described and of the 
venous channels which carry back the purified blood to the general 
circulation. Second, the filtering portion of the kidney, which arises 
from the mesothelium and forms in large part the cortical substance 
which is the arterial portion of the kidney, bringing blood from the 
general circulation for purification. The common, solid tumors of the 
kidney that we have miscalled hypernephroma are, as pointed out by 
Wilson tiue mesotheliomas; that is, malignant neoplasms arising in 
the kidney filter. I think we may agree with Cushny that the kidney 
does not secrete urine, but filters it. The kidney may be aptly 
compared with a separator. The arterial blood enters the kidney 
cortex, the urine is filtered out, and the venous blood passes back to 
the general circulation. Weld, by his experimental injections of 
mediums, demonstrated the physics of the process outlined. The 
The partial failure of the two halves of the kidneys to unite, so that 
the urine, when filtered, is not freely admitted into the collecting 
tubules, produces the so-called congenital polycystic kidneys that 
are eventually associated with chronic nephritis. 

Type 3 nephritis. — Nephritis, the result of living organisms, may 
be called Type 3. True nephritis is concerned with the filter portion 
of the kidney, and the failure to filter out all the bacteria and their 
retention is responsible for the occurrence of one form of the disease, 
which is of great surgical importance. As to just how often such 
infections may be ascending or lymphogenous rather than hematogen- 
ous in origin there is a diversity of opinion. My own opinion is that 
such infections, other than hematogenous, are extremely rare so far 
as the kidney filter is concerned, though it is possible they may be more 
frequent in that part of the kidney devoted to collecting urine. 

Accepting the idea that there is a common form of true nephritis 
which differs from Bright's Types 1 and 2 and is caused by a bacterial 
infection, we quickly see that the effect on the kidney will depend on 
the nature of the bacteria, their number, and on the condition of the 
kidney itself, whether, for example, there is an anomaly present, 
such as hydronephrosis or calculi, which makes the kidney more 
vulnerable. The importance of this has been shown by Cabot and 
Crabtree, who demonstrated that the pus cocci affect the cortex of 



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188 W. J. MAYO 

the kidney and often follow lines of least resistance toward the per- 
iphery, and that the colon bacteria affect the straight collecting tubules 
of the pyramids, extend from them to the pelvis, and there produce a 
pyelitis. Pyogenic infections may lead to cortical abscesses and 
other evidences visible to the eye; but with scanty urinary findings 
beyond a trace of albumin and a few microscopic pus and blood cells, 
the urinary evidences are so slight in the acute stage, as to be over- 
looked unless great care is exercised. In the subacute and chronic 
forms the kidney may be more or less destroyed, and the common 
forms of pyonephrosis will follow. The pyogenic cocci are short 
lived and often are not to be found in the pathologic changes their 
action initiates. On the contrary, colon bacteria, by the production 
of copious, purulent sediment in the urine, give adundant evidence of 
infection without abscess formation in the kidney. Acute nephritis 
(Bright's Type 1) is the result of toxic products, not of living organisms, 
as in diphtherial and scarlatinal nephritis, and the two kidneys are 
equally involved. When the nephritis is the result of living bacteria 
(Type 3) the kidneys may be involved unequally or unilaterally, 
the unilateral infection being ; n the kidney which is more vulnerable 
because of some physical defect. The pus-producing organisms affect 
the kidney much as do tuberculosis bacilli, and those who have studied 
tuberculosis of the kidney will recognize the resemblance. 

Hematogenous nephritis is often caused by cocci found in the skin, 
especially staphylococci from boils, carbuncles, and so forth, and from 
focal infections generally. The staphylococcus is short lived and often 
affects only one kidney. Acute streptococcal infections are most 
malignant. Subacute and chronic streptococcal infections occur 
commonly as a result of septic endocarditis, and appear in the kidney 
as a terminal infection, embolic in character. 

In the fulminating type of hematogenous pyogenic infection, unless 
nephrectomy is performed, death may often result within a few days. 
The acute condition is often confused w4th acute intraperitoneal in- 
fections; on the right side, especially, is the differentiation from 
cholecystitis and appendicitis necessary. This may also be true of 
the less acute form. In the subacute and chronic forms, natural 
processes may localize and sterilize the foci of infection, and the 
patients may fully recover, or partial recovery may later be followed 
by chronic infection, and the kidney will be converted into a pyo- 
nephrosis. The fact should be recalled that septic infarcts rupturing 



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HEMATOGENOUS INFECTIONS OF THE KIDNEY 189 

through the capsule of the kidney are the most common cause of 
perinephritic abscess. 

Bright's disease, both Type 1 and Type 2, is of surgical interest 
only because of complications. But all the nephritides caused by 
living bacteria (Type 3) are of great surgical interest and have, until 
recently, been confused with Bright's disease. Hematogenous kidney 
infection is the one bright picture in a group of maladies that have been 
discouraging in the extreme. The surgeon of today is as greatly 
interested in nephritis as is the internist. 

In reviewing the large mass of literature on nephritis, rather super- 
ficially, it is true, I have been particularly impressed with the clear 
and logical presentation made by Brewer in a series of published 
papers beginning in 1911, in which he demonstrates hematogenous 
pyogenic infections of the cortex of the kidney clinically, experi- 
mentally, and pathologically. In this connection, I wish to comment 
on the value of the contributions of the surgeon to such problems. Ne- 
phritis has been studied largely from a clinical and a postmortem stand- 
point. Clinical observations in these cases are notoriously unreliable, 
while the necropsy shows the terminal conditions that cause death. 
This exposition of terminal change, determined at necropsy, is exceed- 
ingly difficult to interpret in the living, and the final catastrophe 
leading to the death of the patient produces pathologic changes obscur- 
ing those that existea during life. In no other way can I explain the 
various theories and controversies which have marked the history of 
the study of nephritis. The clinician attempts, by study of the urine 
and the symptoms of the patient, to explain the terminal conditions 
found after death, which may not have existed at the time the clinical 
examinations were made. The surgeon, not by reason of greater 
acumen but by opportunity, now furnishes the missing link in the 
investigation which carries the truth, and makes possible an exact 
study of the kidney before the terminal infections, which are encoun- . 
tered at necropsy, obscure the picture. 

Payne and MacNider and Buerger have shown the hematogenous 
origin of certain of the so-called chronic, essential hematurias, demon- 
strating that infection in and about the straight tubules, resulting in 
the development of scar tissue, which interferes with the venous cir- 
culation, causes congestion and varicosity of papillae and leads to rup- 
ture and renal hemorrhage. This gives a pathologic explanation for 
several cases in which we explored to find the cause of renal hemor- 



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190 W. J. MAYO 

rhage, and in which one or more papillae were found to be the seat of 
varicosities. 

I have been greatly interested in the chronic form of hematogenous 
nephritis of bacterial origin. In a number of instances, I have ex- 
plored and found small, cortical, pimple-like collections of fluid in the 
kidney in various stages of sterilization. I have been able to link 
up another most interesting sequel to the condition, namely, the 
occasional deposit of calcium carbonate in such an infected area, 
usually close to or connected with the capsule, which produces a roent- 
gen-ray shadow resembling that of stone. The diagnosis of stone is 
often justified by the history of the acute, severe attack which marks 
the onset of infective nephritis. I have known such deposits of lime 
to form as soon as two months after the primary symptoms. Why 
in some persons, lime is deposited during the process of the cure of 
the infection, I do not know. The kidneys in such cases are often 
painful. Our patients were relieved by the excision of the lime 
masses, and by decapsulation. In several cases, the deposits of lime 
were deeper in the cortex. There are almost no urinary signs or 
symptoms in these cases, as the masses are in the cortex with little 
communication with the collecting parts of the kidney. It is very 
evident, too, that in some painful kidneys, with dense scars in the 
capsule, the origin is similar, and the condition may be relieved by 
decapsulation. I have been slow to admit that capsular compression 
of the kidney could be the cause of symptoms, but I have seen at least 
three cases in which hypertrophy of the remaining kidney within its 
fibrous capsule, after the removal of its fellow for disease, produced 
pain from the stretching of the capsule. The kidneys were low and 
movable, and the patients thin, and I was able to follow the compensa- 
tory hypertrophic enlargement by palpation, and to satisfy myself 
that the hypertrophy caused the pain. 

In our experience, decapsulation has been valuable in this small 
group of cases in which there are scars and lime deposits in the capsule 
of the kidney, and in another group still more rare, that of acute 
nephritis (Bright's Type 1), in which, as pointed out by Morris, the 
operation occasionally enables the kidneys to functionate when 
urinary function has ceased and the patients are apparently in a 
dying condition. For movable kidney, and so forth, we have seen 
no good effect from nephrorrhaphy other than the psychic. 



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HEMATOGENOUS INFECTIONS OF THE KIDNEY 191 

BIBLIOGRAPHY 

I. Bissdl, W. W„ and Le Count, E. R.: A consideration of the relative frequency 
of the various forms of coma with special reference to uremia. Jour. Am. Med. Assn., 
1915. Ixiv, 1041-1045. 

£. Brewer, G. E : The present state of our knowledge of acute renal infections, 
with a report of some animal experiments. Jour. Am. Med. Assn., 1911, Ivii, 179-187. A 
rare type of unilateral hematogenous infection of the kidney. Yale Med. Jour., 1910-1911. 
xvii, 237-252. Observations on acute hsemic infections of the kidney. Am. Jour. Urol., 
1913, ix, 549-570. Hematogenous infections of the kidneys, a summary of our present 
knowledge. New York Med. Jour., 1915, ci, 556-560. 

3. Buerger, L.: Concerning certain types of hemorrhagic nephritis. Med. Rec, 
1918, xciv, 1057-1061. 

4. Bright, Richard: Reports of medical cases with a view of illustrating the symp- 
toms and cure of diseases by a reference to morbid anatomy. London, Longmans 
Green & Co , 1827-1831, 2 vols., xvi, 231 pp.; xl, 724 pp. Cases and observations illus- 
trative of renal disease accompanied with secretion of albuminous urine. Guy's Hosp. 
Rep. 1836, 1: 338-379. Tabular review of the morbid appearances in one hundred cases 
connected with albuminous urine, with observations. Guy's Hosp. Rep. 1836, I: 
3SO-400. 

5. Cabot, H. and Crabtree, E. G: A classification of renal infection with particular 
reference to treatment. Boston Med. and Surg. Jour., 1916, clxxiv, 780-785. 

6. Cushny, A. R.: The Secretion of Urine. New York, Longmans, Green & Co., 
1917, 251 pp. 

7. Morris, H.: Notes on the surgical treatment of affections of the kidney. Ann. 
Surg., 1887, v, 289—305. Surgical diseases of the kidney and ureter, including mal- 
formations and misplacements. New York, Cassell & Co., 1901, ii, 670 pp. 

8. Payne, R. L. and MacNider, W. B.: The surgical problem of unilateral symp- 
tomless hematuria. Jour. Am. Med. Assn., 1916, Ixvii, 918-923. 

9. Rowntree, 1». G. and Geraghty, J. T.: An experimental and clinical study of the 
functional activity of the kidneys by means of phenolsulphohephthalein. Jour. Phar- 
macol, and Exper. Therap., 1909-1910, I, 579-660. 

10. Weld, E. H. : Renal absorption with particular reference to pyelography mediums . 
Thesis submitted to the Graduate Faculty of the University of Minnesota in partial 
fulfilment of the requirements for the Degree of Master of Science in Surgery, June, 
1919. 

11. Wilson, L.. B.: Hypernephromata. Old Dominion Jour. Med. and Surg., 1910, 
x, 2S&-252. 



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RECENT ADVANCE IN THE DIAGNOSIS OF SURGICAL 
LESIONS OF THE KIDNEY* 

W. F. BRAASCH 



Recent advance in methods of diagnosis of surgical conditions of 
the kidney has been largely in the field of roentgenography and renal 
functional tests. Roentgenography of the urinary tract rendered 
opaque to the x-ray by injected mediums is now recognized as an 
indispensable factor in the diagnosis of surgical renal lesions. Its 
development was retarded during several years by the use of opaque 
mediums which caused injury to the injected kidney, namely, the 
salts of colloidal silver. This was largely overcome by the use of 
thorium as suggested by Burns. The occasional toxicity and the 
difficulty of preparation of this solution, however, prevented it from 
being an ideal medium. Although sodium iodid, as suggested by 
Cameron, obviated these objections, it remained for Weld to discover 
that ordinary sodium bromid has all the requisites of the ideal medium, 
since it is thoroughly soluble, non-irritating, non-toxic, easily prepared, 
and inexpensive. As a result, by using this inert medium, pyelo- 
graphy may be employed almost routinely with cystoscopy. There 
is scarcely a lesion in the urinary tract in which it has not proved of 
distinct diagnostic value. Since the interpretation of the pyelogram 
has been quite fully described in recent literature I shall not go into 
detail concerning the various deformities of the pelvic outline. 

With the improvement and standardization of x-ray apparatus 
as well as operative technic, roentgenographic examination of the 
urinary tract has become so wide-spread that there are now but few 
surgeons who do not have access to this invaluable diagnostic aid. 
In the diagnosis of renal lithiasis much progress has been made in the 
interpretation of the numerous confusing shadows which appear 
in the roentgenograms of the urinary tract. Although many of these 

* Presented before the Minn. State Med. Assn., Minneapolis, October, 1919. 
Reprinted from Minn. Med., 19*0, iii. 112-118. 

192 



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DIAGNOSIS OF SURGICAL LESIONS OF THE KIDNEY 193 

shadows may be identified by their contour, character, and position, 
a larg? number are impossible to interpret without the combined aid of 
clinical, laboratory, and cystoscopic data. The greatest accuracy, 
however, can.be obtained only through the combined use of the cysto- 
scope and roentgenograph ic technic, as employed in pyelography. 
The pyelographic data that will enable us to determine whether a 
doubtful shadow is extrarenal or intrarenal are as follows: (1) The 
distance separating the shadow from, (2) the exact relation of the 
shadow to, and (3) the presence of pathologic changes in the pelvic 
outline. 

Shadows appearing in the area of the urinary tract which most fre- 
quently are responsible for error in interpretation are those caused by 
calcareous deposit in the extra-urinary tissue, gallstones, and tuber- 
culous renal caseation. Such shadows may lead either to needless 
exploration of the urinary tract, or they may be erroneously regarded 
as extra-urinary. 

It is well known that a gallstone is, as a rule, not visible in the 
roentgenogram. Nevertheless, as a result of the improvement in 
roentgenographs technic it is being found with such frequency as to 
warrant its consideration in the interpretation of every shadow in the 
right upper abdominal quadrant. The similarity of subjective symp- 
tomatology which not infrequently occurs between renal stone and 
gallstone may render the clinical data of little aid in interpreting such 
shadows. While the character of the gallstone shadow is distinctive 
and often is easily recognized, error in interpretation is easily possible. 
The greatest problem in the x-ray diagnosis of gallstone is to dis- 
tinguish its shadow from that of renal stone. If the gallstone shadow 
is situated in the usual position of the kidney, and, should there be a 
coincidental infection of the urinary tract, the diagnosis may be exceed- 
ingly difficult. On the other hand, a renal stone may not infrequently 
be seen lying well above the twelfth or even the eleventh rib, in the 
usual gallbladder area. Furthermore, the renal stone may assume 
characteristics very similar to those of the gallstone. In short, the 
shadow in the roentgenogram cast by a gallstone and by a renal stone 
may be identical in position and character. The pyelogram is usually 
the best and frequently the only method by which the gallstone may be 
identified. The same data previously named in the identification 
of the extrarenal shadow are applicable in the differentiation of gall- 
stones and renal stones. 



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194 W. F. BRAASCH 

Renal tuberculosis. — Recent literature has emphasized the im- 
portance of recognizing shadows caused by calcified areas in a tuber- 
culous kidney. Although they can frequently be identified by their 
characteristic shadow, the combined clinical and cystoscopic data 
may be necessary for their recognition. The shadows are of three 
types, namely (1) small scattered areas caused by lime deposit in the 
calyces, (2) larger shadows of irregular density, some of which may 
assume the characteristics of renal stone, and (3) casts of a portion or 
even the entire caseated kidney. It is advisable, therefore, to have a 
complete roentgenographs examination of the urinary tract in every 
patient suspected of having renal tuberculosis. 

Shadow localization. — It is of value to the surgeon to ascertain as 
accurately as possible prior to operation the exact location of the stone. 
Approximate localization of the stone shadow in the original roent- 
genogram is frequently possible, particularly if the outline of the kidney 
is distinct. By outlining the renal pelvis in a pyelogram and then 
comparing the position of the stone shadow with that of the pelvic 
outline, the stone can be localized more accurately than in the ordinary 
roentgenogram. The main problem in the localization of the stone is 
to determine whether it is situated in the true pelvis, in a calyx, or in 
the cortex. 

Although the percentage of error in operations for lithiasis has 
been greatly reduced, several difficulties still remain to be overcome. 
The following are the complications which are most frequently en- 
countered at the operating table: 

1. Impossibility of an exact interpretation of the roentgenogram. 

2. The difficulty of locating the stone in the kidney. 

3. Inability to find the stone. 

4. The possibility of overlooking one or more stones when multiple 
stones are present. 

5. The possibility of having fragments of stones broken off or 
loosely connected with the original stone. 

Nothing is more disconcerting than the inability to find a stone in 
the kidney when the various methods of clinical examination have 
definitely shown it to be there. The kidney usually becomes so con- 
gested when brought into the field of operation that searching for a 
small stone may be exceedingly difficult and often fruitless. Moreover, 
it may be difficult to determine from the roentgenogram the exact 
number of stones in a kidney. The shadow may appear to be single 



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DIAGNOSIS OF SURGICAL LESIONS OF THE KIDNEY 195 

when in reality it represents two stones which either overlap or are 
closely approximated. What appears to be a single branched stone 
may be made up of several distinct stones. Again, on the removal of a 
branched or irregular stone, fragments are easily broken off and it may 
be impossible to locate them. At the Mayo Clinic we have recently 
made fluoroscopic examinations of the kidney at the operating table, 
employing small portable x-ray machines which are used by the 
United States Army. By this method we believe that many of the 
difficulties accompanying renal lithotomy will be overcome. 

Renal functional tests. — Although the surgical indications of the 
urinary tract are usually determined by the clinical, roentgenographies 
and cystoscopic data, in many cases renal functional tests may be of 
considerable diagnostic value, and may largely influence surgical 
judgment. Tests of renal function are divided into two general types, 
excretory and retentive. The excretory test is the simpler of the two 
and is possibly the more valuable. Of the various excretory tests, 
the use of phenolsulphonephthalein has proved to be the most practical 
because of the accuracy of its elimination and ease of its administra- 
tion. The original contentions of the authors, Rowntree and Geraghty , 
concerning the application of this test, have in the main proved to be 
correct. In the diagnosis of surgical conditions of the kidney it is 
used in estimating the renal function of both kidneys as in the com- 
bined test, and in the estimation of the secretion from the individual 
kidney as in the differential test. 

Combined phenolsulphonephthalein test. — The phenolsulphoneph- 
thalein test as universally employed consists of the estimation 
of the dye secreted by both kidneys during two hours following its 
appearance in the urine after intramuscular injection of 1 c.c. of 
phenolsulphonephthalein. Its value in certain conditions is unques- 
tionable, but attention should be called to the fact that errors may 
arise which, unless carefully watched, will largely negate its value. 
Such errors are of two types, technical and interpretative. If either 
of these errors occurs, the test is not only worthless, but may even 
be misleading. 

Technical errors. — When the test is employed in a hospital where 
every step can be carefully guarded and the patient kept under 
observation during the time of secretion so that the specimen can be 
completely obtained, the possibility of technical error is not great. 
However, as generally employed in the dispensary, ambulatorium, 



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196 W. F. BRAABCH 

office, or at the bedside, the possibility of error is considerable. In 
our experience errors as follows have been found to occur most 
frequently : 

1. Excessive or insufficient amount of phenolsulphonephthalein 
placed in the syringe for injection. 

£. The loss of a portion of the phenolsulphonephthalein solution 
from the syringe or needle when it is injected. 

3. Abbreviation or extension of the two-hour period of collection 
on the part of the patient. 

4. Loss of part of the urine collected in transferring it into the 
receptacle from which the estimate is to be made. 

5. Retention in the bladder of a portion of the urine secreted 
either because of a pathologic condition or misunderstanding on the 
part of the patient. 

6. Error in laboratory technic, such as insufficient alkalization, 
inefficient interpretation of color values, and so forth. 

7. Clerical errors. 

Because of the many possible sources of error it is evident that a 
single phenolsulphonephthalein test with less than the normal amount 
of secretion must be considered worthless unless checked up by a 
second test. 

Errors of interpretation. — Without placing an arbitrary figure 
which would govern in every case, as a general rule, a patient having 
a function of less than 30 per cent should be observed very carefully 
before advising operation. The possibility of retained urine at the 
time of the test from an overlooked prostate, diverticulum, sacculated 
ureter, or hydronephrosis must always be considered. However, 
even though the phenolsulphonephthalein secretion is lower than 
SO per cent, it should not necessarily contra-indicate operation. It 
must be remembered that any renal functional test gives an index of 
renal activity at the time of examination but not what the kidneys 
are capable of when pathologic conditions have been corrected. This 
is particularly true in the presence of lithiasis; the reflex irritation 
from a stone may lower the function of one or both kidneys to an 
alarming degree. When, however, the cause has been removed it is 
not unusual to observe the renal function return to normal. 

The assurance derived from a normal combined phenolsulphone- 
phthalein test, when one kidney is definitely proved to be destroyed, 
is of great value. On the other hand, when the x-ray or clinical 



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DIAGNOSIS OF SURGICAL LESIONS OF THE KIDNEY 197 

examination indicates that one kidney is diseased, it cannot be inferred 
from a normal combined phenolsulphonephthalein test that the other 
kidney is present and normal. As an illustration; when a limited 
pathologic lesion such as a small stone, hydronephrosis, or even a 
limited area of tuberculosis is present in a single or solitary kidney, 
the combined phenolsulphonephthalein test may be quite normal. 
If it is inferred from this that another kidney is present the results 
at operation may be disastrous. The possibility of bilateral disease 
existing in the presence of a normal phenolsulphonephthalein secretion 
cannot be excluded since it has been repeatedly noted with bilateral 
tuberculosis, bilateral renal lithiasis, polycystic kidney, and so forth. 
Differential functional test. — A differential functional test is 
the method of estimation of phenolsulphonephthalein secretion col- 
lected from the individual kidneys by means of the ureteral catheter 
during a period of from fifteen to thirty minutes following intravenous 
injection. Primarily the test was used to determine the state of 
efficiency of the supposedly well kidney. It is, however, of even 
greater value as an aid to diagnosis of renal lesion. As with the com- 
bined test, the possibilities of error in technic and interpretation must 
be considered. It is necessary that the dye be injected intravenously 
and not intramuscularly, otherwise the rate of secretion will be greatly 
retarded. If given intravenously the dye will appear in the urine 
within four or five minutes after injection, and an average of 15 and 
30 per cent is secreted from each normal kidney in fifteen and thirty 
minutes respectively. The amount of dye, however, is not always 
constant and may be influenced by hypersecretion in a nervous person, 
which will cause a much larger amount of dye to be secreted, or by 
hyposecretion, which may be caused by reflex inhibition of secretion 
from catheter irritation. Another source of error may arise unless 
due allowance is made for return flow of the urine alongside the ureteral 
catheter into the bladder. It is necessary carefully to estimate the 
amount of dye which is found in the bladder at the end of the fif teen- 
or thirty -minute period. * A recent suggestion of one of my associates 
(Peterson) has proved to be of practical value in this complication. 
He suggested a so-called "concentration test" which consists of estimat- 
ing the dye in from 2 c.c. to 5 c.c. of the urine collected from each 
kidney and making a relative comparison. If the same amount of 
dye is found in both sides, even though a large amount of return flow 

* When more than 10 per cent of the total dye secreted is found in the return flow 
the value of the test is greatly diminished and may even he completely destroyed. 



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198 W. F. BRAASCH 

urine is in the bladder, we may infer that both kidneys are functionat- 
ing equally. 

The value of methylene blue and indigo-carmin as an aid to ascer- 
taining renal function must, however, also be recognized. As a rough 
test, particularly when one or both kidneys cannot be catheterized 
or when it seems inadvisable to do so, it may be invaluable. Thomas 
has recently added to the value of the blue test by his method of 
making a quantitative estimate of the dye secreted. It is, however, 
not of such diagnostic value, nor is it so accurate in ascertaining the 
degree of renal function as the phenolsulphonephthalein test. It may 
occasionally be desirable to employ both tests simultaneously. Peter- 
son has shown that the blue color need not interfere with the phenol- 
sulphonephthalein estimate. He overcomes this difficulty by simply 
alkalizing the urine which removes the blue color and permits an 
accurate phenolsulphonephthalein estimate. 

Retention tests. — Estimation of the degree of retention in the blood 
of metabolic end products such as uric acid, urea, and creatinin has of 
recent years been placed on a practical basis. This is largely the result 
of the work of American investigators such as Folin and Denis, Mar- 
shall, Myers and Fine, and others. The estimation of the urea nitro- 
gen content of the blood has been most widely employed in surgical 
conditions of the urinary tract. It is generally recognized that an 
estimation of 40 mg. of urea nitrogen for each 100 c.c. of blood would 
indicate a guarded prognosis, and when it reaches more than 100 mg. 
the prognosis is very grave. More recently it has been found that 
creatinin when retained in the blood in amounts of more than 2.5 mg. 
is indicative of serious renal disease, and when more than 5 mg. is 
retained, the termination is usually fatal. 

Retention tests are best employed in conjunction with the elimina- 
tion tests. They are of considerable routine value in checking the 
results of the elimination tests and calling attention to possible techni- 
cal errors in their estimation. Because of inability to obtain complete 
data of secretion, retention tests may offer the only method with which 
renal function can be estimated. 

Bacteriology. — Probably the most important recent contribution to 
the bacteriology of the kidney is that made by Cabot and Crabtree, 
who have demonstrated that the clinical course of an infectious renal 
lesion is largely dependent on the identity of the bacteria. The colon 
group of bacilli tends to produce non-suppurative renal changes, while 



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DIAGNOSIS OF SURGICAL LESIONS OF THE KIDNEY 199 

the pathogenic bacteria, notably the cocci, tend to produce suppurative 
nephritis and abscesses. Lesions caused by the colon group are 
usually non-surgical and, in the early stages, are amenable to treat- 
ment, whereas a coccus infection of the kidney is distinctly a surgical 
condition. The coccus infections usually predominate in the cortex. 
The importance of making a bacterial investigation of the urine in 
cases of acute renal infections is self-evident. 

The subject of renal infection, particularly as to the path of trans- 
mission of the original infection, has in recent years engaged the atten- 
tion of numerous observers. Sweet, Eisendrath, and others have 
performed experiments which would go to prove the existence of an 
ascending or lymphatic route, while Cabot and Crab tree maintain that 
the infection is always hematogenous. It is probable that both 
methods of infection may exist although the latter is by far the more 
frequent. However, all observers are now quite convinced that renal 
infection is secondary to some other active focus of infection and that 
it is of primary importance to exclude the possibility of such a focus 
in the tonsils, teeth, prostate, seminal vesicles, and so forth. 

Our knowledge concerning certain phases of renal physiology has 
recently been considerably augmented. The use of colloidal silver in 
the renal pelvis demonstrated to us the absorptive power of the renal 
parenchyma from the pelvis. This has been experimentally corrobo- 
rated by Burns, and by Weld. It has been demonstrated that 
phenolsulphonephthalein injected into the renal pelvis is secreted 
from the other kidney within five minutes. This fact has been taken 
advantage of in the treatment of pyelonephritis by injecting large 
amounts of solutions of silver nitrate and other antiseptics into the 
renal pelvis. It may be inferred that not alone the pelvis will be 
affected, but the antiseptic solution will enter the renal tubules and 
come in contact with diseased areas in the parenchyma itself. 

Theories as to the probable etiology of symptomless unilateral 
renal hematuria, or the so-called essential hematuria, have recently 
been modified. It was formerly thought that this condition was due 
to a true nephritis (Bright's Type 1 according to the classification of 
nephritis by W. J. Mayo). Recently, however, the condition has 
been regarded as frequently the result of an insidious chronic infection 
of the renal papillae. Payne and MacNider, and Buerger have demon- 
strated that sections of the renal papillae show evidence of infectious 
changes together with varicose condition of the venous capillaries. 



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200 W. F. BRAASCH 

It would seem that the circulatory changes in the papilla? are the direct 
result of the infection. This theory is further corroborated by the 
fact that permanent cessation of hematuria may be brought about 
by means of injecting strong solutions of silver nitrate into the renal 
pelvis. The diagnosis of this interesting condition is rendered fairly 
exact by demonstrating the outline of a normal pelvis in the roentgeno- 
gram and by demonstrating an equilateral normal phenolsulphone- 
phthalein output. 

Cystoscopic technic. — The use of the cystoscopy has, like the use of 
the roentgenograph, been widely extended in recent years. Many im- 
provements have been made in the various instruments employed so 
that its value in diagnosis and treatment of diseases of the urinary 
tract has been greatly augmented. In the diagnosis of stones in the 
ureter the wax-tipped catheter which was suggested by Kelly many 
years ago, and which later fell into disuse, has recently enjoyed a 
renaissance. The method is as follows: Melted beeswax is placed 
on a ureteral catheter which is introduced up to or past a ureteral stone. 
If scratch marks result, they should be of considerable diagnostic 
value. Its practical application, however, particularly with the type of 
cystoscopes now in vogue, has not proved so satisfactory as it might 
seem. It often happens, particularly with small stones, that either 
no scratch appears or it is too indefinite for exact interpretation. 
Furthermore, scratches caused by the cystoscope may be difficult 
to identify. On the other hand, if properly employed the wax catheter 
should give data of considerable value. 

Hunner has called our attention to the existence of wide strictures 
or infiltrations of the ureteral wall which have been overlooked in the 
past. He makes his diagnosis entirely from the obstruction or rather 
the hang encountered by a large wax bulb as it is passed through the 
strictured area. The frequency with which such a stricture occurs and 
the variety of symptoms it causes will make this condition one of pri- 
mary importance if the findings of Hunner are corroborated by future 
investigation. The scarcity of pathologic and anatomic confirmation, 
however, in a measure negates the value of this contribution. Hunner 
furthermore claims that stones found in the ureter are usually formed 
in the dilated portion above a stricture rather than primarily in the 
kidney. Although the suggestion is of considerable interest it, 
nevertheless, lacks confirmation and seems improbable because of the 
following reasons: (1) The presence of a strictured area in the ureter 



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DIAGNOSIS OF SURGICAL LESIONS OF THE KIDNEY 201 

below a stone has not been corroborated by other surgeons. (2) 
Ureteral catheterization following operation fails to demonstrate 
strictures. (3) The small percentage of ureteral stones that recur even 
though no attempts are made to treat a stricture. 

In conclusion I would say that recent progress in diagnosis of 
surgical conditions involving the kidney has indeed been considerable. 
The interest in the subject by both internist and surgeon is widespread 
since the close relationship of renal diagnosis to that of the surrounding 
organs is realized by both. Today there are but few medical groups 
that do not have access to such methods of diagnosis as I have 
described. 

BIBLIOGRAPHY 

1. Buerger, L.: Concerning certain types of hemorrhagic nephritis. Med. Rec., 

1918. xciv, 1057-1061. 

2. Burns, J. E.: Thorium — a new agent for pyelography. Bull. Johns Hopkins 
Hasp., 1916, xxvii, 157-164. 

3. Cabot, H. and Crabtree, £. G. : The etiology and pathology of non-tuberculous 
renal infections. Surg., Gynec. and Obst., 1916, xxiii, 495-537. 

4. Cameron, D. F.: Aqueous solutions of potassium and sodium iodids as opaque 
mediums in roentgenography. • Preliminary report. Jour. Am. Med. Assn., 1918, lxx, 
754-755. 

5. Eisendrath, D. N. and Kahn, J. V.: The r61e of the lymphatics in ascending 
renal infection. Jour. Am. Med. Assn., 1916, lxvi, 561-564. 

6. FoHn, O. and Denis, D. : Protein metabolism from the standpoint of blood and 
tissue analysis. On uric acid, urea and total non-protein nitrogen in human blood. 
Jour. Biol. Chem., 1913, xiv, 29-42. 

7. Hunner, G. L.: Ureteral stricture — report of 100 cases. Bull. Johns Hopkins 
Hasp., 1918, xxix, 1-15. 

8. Kelly, H. A.: Ureteral calculus. Its diagnosis by means of the wax-tipped 
bougie. Jour. Am. Med. Assn., 1900, xxxiv, 515-517. 

9. Marshall, E. K.: A new method for the determination of urea in blood. Jour. 
Biol. Chem., 1913, xv, 487-496. 

10. Mayo, W. J.: Hematogenous infections of the kidney. Jour. Am. Med. Assn.. 

1919. lxxiii, 1023-1026. 

11. Myers, V. C. and Fine, M. S.: The metabolism of creatine and creatinine. 
The relationship between creatine and creatinine in autolyzing tissue. Jour. Biol. 
Chem., 1915, xxi, 593-599. 

12. Payne, R. L. and MacNider, W. B.: The surgical problem of unilateral symp- 
tomless hematuria. Jour. Am. Med. Assn., 1916, Ixvii, 918-923. 

13. Peterson, A.: A preliminary report on the simultaneous use of indigo-carmin 
tad phenolsulphonephthalein tests in surgical diseases of the kidneys. Surg., Gynec. 
sad Obst., 1917, xxv, 561-565. 

14. Rowntree, L. G, and Geraghty, J. T.: An experimental and clinical study of 
the functional activity of the kidneys by means of phenolsulphonephthalein. Jour. 
Pharmacol, and Exper. Therap., 1909-1910, 1. 579-660. 



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StWt W. F. BRAASCH 

15. Sweet, J. £. and Stewart, L. F.: Ascending infection of the kidneys. Surg., 
Gynec. and Obst., 1914, xviii, 460-469. 

16. Thomas, 8. A. and Birdsall, J. C: Comparative results of various functional 
kidney tests, based on a series of cases. Jour. Am. Med. Assn., 1917, lxix, 1747-1751 

17. Weld, £. H. : The use of sodium bromid in roentgenography. Jour. Am. Med. 
Assn., 1918, lxxi, 1111-1112. 



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REXAL FLUOROSCOPY AT THE OPERATING TABLE" 

W. F. BRAASCH AND R. D. CARMAN 



Surgical treatment of renal lithiasis is rendered unsatisfactory 
by complications as follows: 

1. The difficulties of an exact interpretation of the roentgenogram. 

2. The difficulty of locating the stone. 

3. Inability to find the stone. 

4. The possibility of overlooking one or more stones when multiple 
stones are present. 

5. The possibility of having fragments of stones broken off or 
loosely connected with the original stone. 

It is true that a large number of renal stones are easily diagnosed 
and removed. This is particularly true of stones with a diameter 
of two or more centimeters, situated in the pelvis. When the stone 
is small and fla*, however, or when it is deep in the calyx pro- 
jecting into the cortex, palpation of the stone may be impossible, 
even when the kidney is brought out of the incision. The possibilities 
of error in diagnosis have been greatly reduced through the aid of 
cystoscopy and pyelography. Nevertheless, it may be quite impossible 

(1) to differentiate extrarenal shadows which are obscured by the 
renal pelvis outlined in the pyelogram; (2) to identify small stones in 
the kidney that have not caused any pathologic changes in the outline 
of the renal pelvis; and (3) to recognize calcareous patches which are 
occasionally found in the kidney cortex and differentiate them from 
actual stone. 

The preoperative localization of the shadow has been made fairly 
accurate (1) by interpretation of the size and shape of the shadow; 

(2) by the relation of the kidney to the shadow; and (3) by means of 
pyelography. Stones with a triangular or branched outline are 
almost always situated in the pelvis. If the outline of the kidney is 
definitely determined by the roentgenogram the position of the stone 
may frequently be approximately inferred. Although pyelography 

♦ Reprinted from Jour. Am. Med. Assn., 1919, lxxiii, 1751-1752. 

203 



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204 W. F. BRAASCH AND R. D. CARMAN 

will usually afford more accurate data in the localization of the stone, 
it may also be inexact. It may be impossible to determine whether 
the stone is free in the upper calyx, impacted in the end of the calyx, 
or projecting partially or wholly into the cortex. 

Nothing is more disconcerting than the inability to find a stone in 
the kidney when the various methods of clinical examination have 
definitely shown it to be there. In the presence of a hydronephrosis, 
particularly when the dilatation is largely confined to the calyces, a 
stone of fair size may be secreted in the bottom of a calyx and defy 
discovery by the palpating finger. A stone lodged in the end of a 
calyx which is shut off from the pelvis by inflammatory or cicatricial 
change may escape palpation. When the stone is in the cortex the 
venous congestion of the kidney consequent to delivery may render 
its palpation exceedingly difficult. Needling, while occasionally of 
aid, is more often of doubtful value and since it causes considerable 
damage to the kidney tissue should be discouraged. Cortical in- 
cision, when extensive and multiple, is objectionable because of con- 
sequent destruction of renal tissue and the danger of subsequent 
hemorrhage. 

It may be very difficult to determine, from the roentgenogram, 
the number of stones in a kidney. The shadow may appear to be 
single when in reality it represents two stones which either overlap 
or are closely approximated. What appears to be a single branched 
stone may be made up of several distinct stones. The shadow may be 
misleading when it has an evident projecting branch, which is seemingly 
explained by irregularity in the stone removed; a second small stone 
which actually caused the shadow may be easily overlooked. On the 
other hand, the shadow of an irregular stone may assume an outline 
and consistency suggestive of several stones. When only one stone 
is found at operation, the surgeon, after persistent search with more 
or less damage to the kidney, is still in doubt as to a remaining stone. 

On the removal of branched stones, fragments are easily broken off, 
particularly when the ends are impacted in minor calyces. Examina- 
tion of the stone removed may show this, but more often it cannot 
be determined definitely. Rough stones that are extracted with 
difficulty may have a soft fragment wrenched off. Occasionally 
soft stones have a putty-like mass of crystals adjacent to them which 
may later form the nucleus of another stone. 

Because of the difficulties in interpreting the roentgenograms and 



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RENAL FLUOROSCOPY AT THE OPERATING TABLE 205 

determining the number and location of stones, surgery for renal lithia- 
sis is frequently an unsatisfactory procedure. Many so-called cases of 
recurrences of renal lithiasis are due to the fact that the stone or stones 
have not been completely removed at the time of operation. Whether 
or not stones or their fragments have been overlooked may often be 
determined by a roentgenogram made following convalescence from 
operation. This may give the desired information; but if a shadow 
persists the patient's condition will not be improved, and the surgeon 
is then faced with the awkward necessity of being obliged to advise 
either an immediate or postponed operation. An immediate operation 
is rendered difficult by the patient's condition, by changed conditions 
of the perirenal tissues, the possibility of renal hemorrhage, and so 
forth. If the operation is postponed the patient may neglect the 
condition until the kidney becomes seriously damaged. 

Realizing the difficulties involved it is apparent that a more accu- 
rate method of examination of the kidney at the time of operation is 
desirable. Unfortunately the usual roentgenographs examination 
at the operating table is an awkward procedure and requires too much 
time. It would seem that if fluoroscopic examination when the kidney 
is brought out of the wound could be made practical the various 
difficulties surrounding lithotomy would be readily overcome. Tak- 
ing advantage of the recent improvement made in fluoroscopic appara- 
tus and the simplification of roentgenographic machines, we have 
employed the apparatus described herewith. 

Apparatus. — The apparatus used for making fluoroscopic observa- 
tions of the kidney at the operating table is essentially the same as 
that used in the base and field hospitals of the army, but with certain 
minor changes which make it adaptable to civilian practice. 

Such instruments (machines) consist of a transformer and auto- 
transformer enclosed in a metal cabinet mounted on large casters 
for portability. To the cabinet is attached a tube stand with a hori- 
zontal arm having universal joints for supporting the tube. The 
tube is of the Coolidge radiator self -rectifying type mounted in a lead 
glass shield. 

The unit is small and compact, requiring less than two and one- 
half square feet of floor space. It is of light weight, portable, and has 
no moving parts which might cause noise and vibration. The current 
is turned on and off either by a hand or floor switch. These portable 



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206 W. F. BRAASCH AND R. D. CARMAN 

units may be operated from the ordinary lamp socket without special 
wiring. 

Technic. — As an essential preliminary, the x-ray operator should 
wear goggles of smoked glass for about fifteen minutes before the 
observation is to be made in order that he mpy have the necessary 
dark-accommodation and retinal perception. The x-ray unit should be 
placed as close to the operating table as possible, and the rays focused 
through a small diaphragm so that they will pass through the delivered 
kidney onto the fluoroscopic screen. When the fluoroscopist is 
ready to make the x-ray examination, the hooded screen held in the 
left hand is placed over the eyes, and the goggles are removed. The 
current is turned on by means of a foot switch. In the right hand is 
held a sterilized metal- tipped rod 18 inches long which the fluoro- 
scopist accurately points to the stone shadow in the kidney. The 
exposure is short, requiring little more than a flash. The various 
details can be easily arranged so that there is no interference with 
surgical asepsis. 



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SURGICAL RENAL TUBERCULOSIS: THE PROGNOSIS* 

W. F. BRAASCH 



Several factors affecting the prognosis in cases of surgical renal 
tuberculosis have not as yet been definitely determined. Probably 
the most important of these are: Age, sex, coincident tuberculosis in 
other tissues, duration of symptoms, degree of involvement of the 
bladder and kidney, and bilateral renal disease. 

According to the surgical records of the Mayo Clinic 532 persons 
were operated on for renal tuberculosis from Jan. 1, 1894, to Jan. 1, 
1918. During this period about 85,000 patients were operated on; 
thus the incidence of surgical renal tuberculosis may be estimated as 
0.6 per cent. A previous review 1 has been made of the postoperative 
records of a portion of these cases, but the present data have been 
derived from more complete records and a larger number of cases. 

The total number of patients (532) was employed in the estimation 
of many of the general statistics. Among this number were 16 
patients who were known to have bilateral renal tuberculosis and were 
therefore not considered in the survey of postoperative results. Statis- 
tics bearing on postoperative results were based on the postoperative 
records of patients heard from either by correspondence or by personal 
examination. This number included 435 patients (84.3 per cent) of 
those operated on. It will be noted that only the postoperative 
records of patients operated on prior to Jan. 1, 1918, were studied. 
In considering the influence of the different complications it was 
found that more detailed data were available in 346 cases in which 
operations were performed from Jan. 1, 1912, to Jan. 1, 1918, inclusive. 

The greatest incidence of surgical renal tuberculosis (69 per cent 
of the total) occurred between the ages of 20 and 40. The largest 
number of cases (37 per cent) was in the third decade. The condition 
is rarely found in the first and seventh decades. When tuberculous 

* Presented before the American Association of Genito-Urinary Surgeons, Atlantic 
City, June, 1919. 

Reprinted from Am. Jour. Med. So., 1920, clix, 8-19. Copyright, 1920, by Lea 
«nd Febiger. 

207 



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208 W. F. BRAASCH 

infection of the kidney does occur in children, it is usually in conjunc- 
tion with tuberculosis disseminated in other tissues so that operation 
is inadvisable. Nephrectomy in children should not be done with the 
first onset of symptoms; it is advisable only when it is evident that 
the active tuberculous infection is localized in the kidney. 

Table 1. — Age 
Patients operated on 532 

Per cent 

2 patients to 10 years 0.4 

S7 patients 11 to 20 years 6.9 

197 patients 21 to SO years 37.0 

168 patients 31 to 40 years 32 .0 

89 patients 41 to 50 years 16 .7 

36 patients 51 to 60 years 6.7 

3 patients 61 to 70 years 0.6 

Patients with postoperative data 435 

Reported dead Per cent 

32 patients 11 to 20 years 9 28.1 

161 patients 21 to 30 years 41 26.2 

137 patients 31 to 40 years 26 18.9 

75 patients 41 to 50 years 20 26.6 

27 patients 51 to 60 years 7 25. 9 

3 patients 61 to 70 years 1 33.3 

The influence of age on the ultimate prognosis is of comparatively 
little significance and the general mortality average remains fairly 
constant in the various decades. The late mortality during the 
third decade is somewhat lower than that during the other decades, 
but the difference is not great enough to warrant any definite prognostic 
distinction. In the first and last decades too few cases are involved 
to give the mortality percentage any accurate value. 

Table 2.— Sex 

Per cent 

Patients 532 

Males 338 63.5 

Females 194 36.5 

Patients with postoperative data 435 

Deaths 105 

Males 75 27.5 

Females ^ 30 18.4 

The greater number of male patients is in keeping with the pre- 
ponderance of male patients in cases of other chronic infections of the 



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SURGICAL RENAL TUBERCULOSIS 209 

kidney. The relative mortality is somewhat higher in the male. 
The relative duration of preoperative symptoms is practically the 
same in both sexes. 

Table 3. — Coincident Lesions 

Per cent 
Patients with renal tuberculosis operated on from 

1912-1918 346 

Patients with coincident lesions 244 71 .0 

Patients with complete postoperative data 201 

Patients who died 33 16 . 4 

Patients with one lesion 89 

Patients with one lesion who died 14 15 .7 

Patients with two lesions 56 

Patients with two lesions who died 9 17 . 8 

Patients with three lesions 39 

Patients with three lesions who died 5 12.8 

Patients with more than three lesions 17 

Patients with more than three lesions who died.. 5 29.4 

Evidence of tuberculosis in other parts of the body, either healed 
or active, was found in 244 of the 346 patients (71 per cent) operated 
on since 1912. In the examination of a patient with suspected renal 
tuberculosis a thorough search for such complications is necessary. 
In fact, it is questionable whether renal tuberculosis ever occurs 
without coincident tuberculosis in some other tissue, and which may 
not be apparent on casual examination. That such complications 
exert but little influence on the ultimate prognosis is evidenced by the 
fact that the mortality percentage in our cases was even lower when 
coincident tuberculosis was noted than that of the general average. 
The occurrence of coincident tuberculosis, particularly when healed 
or dormant, does not necessarily render the prognosis less favorable; 
in fact, it may be regarded as an evidence of good resistance power 
on the part of the patient. In reviewing the postoperative results 
of the patients with complications it is of interest to note that when 
multiple lesions occurred the percentage of recovery was relatively 
as great as when only one lesion was noted. The only exception 
occurred where multiple active complications existed as a part of a 
generalized tuberculosis. The individual influence of the various 
coincident tuberculous lesions will be considered separately. 

Pulmonary tuberculosis is one of the most common complications 
occurring with renal tuberculosis. Fortunately it is usually found 
in a chronic or healed form. Renal tuberculosis is not a common 
complication of active pulmonary tuberculosis. It occurred as a 

'19-H 



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210 W. F. BRAASCH 

coincident infection in less than 5 per cent of our patients. As a 
part of a general or a miliary tuberculosis the coincident infection 
probably occurs more frequently. Pulmonary tuberculosis as a sec- 
ondary complication of renal tuberculosis is of relatively infrequent oc- 
currence although it is a factor in the late mortality after nephrectomy. 

Table 4. — Coincident Pulmonary Tuberculosis 

Per cent 

Patients operated on for renal tuberculosis, 1912-1918 346 

Patients having complete postoperative information 298 

Patients who died 44 14 .7 

Patients having complete x-ray and clinical examination of 

chest 300 

Patients having definite evidence of pulmonary involvement. 81 27 .0 

Patients having definite active tuberculosis 16 5.3 

Patients having definite active tuberculosis and complete 

postoperative information 13 

Patients who died (none in hospital) 6 46. 3 

Patients having doubtful active tuberculosis 17 

Patients having doubtful active tuberculosis and complete 

postoperative information 16 

Patients who died , 3 18.7 

Patients having definite healed tuberculosis 26 

Patients having definite healed tuberculosis and complete 

postoperative information 21 

Patients who died 2 9.5 

Patients having indefinite clinical or indefinite evidence of 

previous pulmonary involvement 22 

Patients having complete postoperative information 19 

Patients who died 1 5.2 

Complete x-ray and clinical examinations were made of the chest in 
300 patients. Evidence of pulmonary tuberculosis was found in 84 
(28 per cent). The cases were divided into four groups: (1) Definite 
active tuberculosis; (2) doubtful active tuberculosis; (3) definite 
healed tuberculosis; and (4) doubtful clinical or x-ray evidence of 
previous involvement. A number of patients in whom the physical 
and x-ray data were indefinite were not included. 

In Group 1 were 16 patients (4.6 per cent) of the total number 
operated on. Fourteen were males and 2 were females. The mor- 
tality of this group as might be expected was very high; 6 (37.5 per 
cent) of the patients died. However, since almost two-thirds of the 
patients recovered it is evident that active pulmonary tuberculosis 
does not necessarily exclude operation in cases of renal tuberculosis, 
but, on the contrary, offers a fair chance for recovery. In the majority 



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SURGICAL RENAL TUBERCULOSIS 211 

of these cases the active pulmonary lesion was confined to compara- 
tively limited areas, diffuse miliary involvement being regarded as 
excluding operation. In several cases, although the lesions were 
quite extensive and even bilateral, the general condition of the patients 
warranted operation. In several cases of well-advanced pulmonary 
tuberculosis the advisability of operation was doubtful, but it was 
rightfully argued that an operation offered the only chance of re- 
covery. The most important factor in determining the advisability 
of operation was the patient's general condition. None of the patients 
died in the hospital, or immediately following operation, showing 
that the anesthetic (ether in every case) even in the presence of active 
pulmonary tuberculosis had no immediate harmful effect. 

Group 2 probably includes a small number of patients with limited 
active lesions. The mortality was approximately average. In 
Groups 3 and 4 the mortality was unusually low. From this it may 
be argued that patients with healed pulmonary tuberculosis have 
developed high resisting powers against the tuberculous infection, 
and that complicating renal tuberculosis is an evidence that the 
resistance of patients is only temporarily lowered at the time of the 
renal infection. 

Table 5. — Genitalia 

Per cent 

Male patients operated on (1912-1918) 234 

Lesions in genitalia 171 73.0 

Complete postoperative data 141 

Patients reported dead 26 18.4 

Epididymectomy prior to operation 26 

Epididymectomy after operation 24 

Patients who died following epididymectomy 

after operation 3 12 .5 

Coincident tuberculosis in the genitalia rarely occurs in the female; 
it was noted as definite in 171 (73 per cent) of the group of 234 male 
patients. Twenty-six of these patients (18.4 per cent) died, 13 during 
the first year. The late mortality is therefore not greatly influenced 
by this complication. The high percentage of recoveries among the 
patients in this group who had clinical evidence of tuberculosis in the 
prostate and seminal vesicles should contra-indicate surgical treat- 
ment of these organs. It is evident that spontaneous healing must 
occur in the majority of instances. On subsequent examinations the 
prostate and vesicles are usually diminished in size, and either hard 
and fibrous or apparently practically normal. Acute suppuration in 



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212 W. F. BRAASCH 

the prostate and seminal vesicles is unusual. Surgical treatment of 
the tuberculous prostate is indicated only in certain cases of protracted 
vesical irritation or in the presence of suppuration. 

Tuberculosis in the epididymis and testicle should be treated 
surgically because of the frequency of suppuration and because the 
process does not usually become dormant and disappear. Further- 
more, a tuberculous epididymis must always be regarded as a possible 
focus of general infection. Epididymectomy was done on 50 patients 
in the series: 26 prior to nephrectomy and 24 following nephrectomy. 
Three (12.5 per cent) of the last group are reported dead. 

Table 6. — Bones and Joints 

Per cent 

Patients with lesions 21 6.0 

Patients with complete postoperative data 19 

Patients with lesions described as active 10 57 .8 

Patients reported dead 1 5.2 

Patients with spondylitis 17 5.7 

Patients with active spondylitis 3 

Patients reported dead (1 active spondylitis) 2 11.7 

Tuberculosis, either healed or active, involving the bones and joints, 
is not unusual with renal tuberculosis. A review of our records 
shows 21 (6 per cent) such cases. Of this number 10 were described 
as active. Four (13.3 per cent) of the patients are reported dead. 
Coincident lesions in the bones, even though active, have little or no 
bearing on the prognosis provided it is not a part of general acute 
tuberculosis. 

To the group of complications involving the bone should be added 
the cases of spondylitis. Fourteen patients were suffering with chronic 
and three with active spondylitis. Two of the former and one of the 
latter are reported dead, evidence that chronic spondylitis does not 
greatly affect the ultimate result. Active spondylitis, particularly 
in the presence of other tuberculous lesions, will necessarily make the 
prognosis much more serious, but it does not contra-indicate operation. 
One of the patients with an active process operated on six years ago 
is living, in a fair degree of health. In a number of such patients 
observed the condition was regarded as inoperable either because 
of their general health or the presence of other active complications. 

Adenitis. — In but 19 (6.4 per cent) patients was there any well- 
marked evidence of tuberculous adenitis. In the majority of these 
only a few glands were involved, and in none sufficiently to require sur- 



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SURGICAL RENAL TUBERCULOSIS 213 

gical intervention. Two of the 19 patients (10 per cent) are reported 
dead, indicating that this complication has no bearing on the prognosis 
other than to show the high resistance on the part of the patient. 

Table 7. — Hemoglobin 

Patients having less than 80 per cent 73 

Patients reported dead 7 (9 per cent) 

Average duration of bladder symptoms (2 cases without) ... 2 years, 9 months 

Patients with 50 per cent or below (one died) 8 

Anemia secondary to renal tuberculosis is frequently noted. Its 
incidence in our series was 25 per cent. As a rule the degree of anemia 
is not marked. The reduction in hemoglobin is seldom caused by 
the loss of blood from hematuria. It is not in proportion to the dura- 
tion of symptoms of the bladder since a number of patients with low 
hemoglobin had symptoms of only a few months' duration. The 
average duration was two years and seven months, which is about the 
average of all cases. The greatest reduction of hemoglobin is noted 
with extensive renal suppuration when absorption of toxins was 
evidently the cause. The degree of hemoglobin gives no index to 
prognosis; 8 patients had 50 per cent hemoglobin, or below, of whom 
1 died. Seven patients in the series (9 per cent) are reported dead. 

Table 8. — Bladder Involvement 
Patients Dead 

Degree 1 55 8 

Degrees 92 9 

Degree S 71 16 

Degree 4 43 7 

The pathologic condition in the bladder as noted on cystoscopic 
examination in this series is estimated on a scale of 1 to 4; 1 slight 
involvement; 2 moderate; 3 marked, and 4 extreme. It was found 
that the patients were about equally divided between moderate (1 and 
2) and marked (3 and 4), the largest single group being 3. The average 
duration of preoperative symptoms when the degree of inflammation 
was scaled 3 and 4 was two and one-half years, and when it was scaled 
1 and 2 it was only one and one-half years. When the preoperative 
degree of bladder inflammation was slight or moderate (1 and 2) it 
was found that immediate postoperative improvement in bladder 
symptoms occurred in 20 per cent, whereas with bladder inflammation 
graded 3 and 4 immediate improvement was noted in only 10 per cent. 
The late mortality in cases of moderate bladder involvement (1 and 2) 




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214 W. F. BRAASCH 

was practically 11 per cent, whereas with advanced involvement 
(3 and 4) it was 20 per cent or twice as great. Although the renal 
disease usually has existed longer in cases of marked bladder involve- 
ment, the difference in involvement is evidently more dependent on 
the virulence of the infection than on the duration of symptoms. 

Table 9. — Degree of Pathology 

Per cent 

Patients with complete postoperative data (191&-1918) . 298 

Patients dead 44 14.7 

Patients with limited lesion 37 

Patients dead 2 4.5 

Patients with advanced lesion 159 

Patients dead 25 15.7 

Patients with large pyonephrosis 58 

Patients dead 12 20.6 

Patients with occluded tuberculosis 44 

Patients dead 5 11.3 

The conditions of the kidneys removed were divided into four 
groups: (1) Slight lesions; (2) advanced lesions; (3) complete destruc- 
tion, described as advanced pyonephrosis; and (4) occluded (caseated) 
tuberculosis. The lesions in the first group were slight, consisting of 
limited single areas, or multiple early lesions. The mortality in this 
group (4.5 per cent) was the lowest and seems to refute the necessity 
of the patient's development of immunity before the kidney is re- 
moved. In by far the largest number of patients the pathologic condi- 
tion of the kidneys was described as advanced (Group 2). Multiple 
areas involving from one to two- thirds of the kidney substance were 
usually found. In Group 3 cases the process has generally existed for so 
long a time that extensive suppuration has occurred. The mortality 
is greatest and is probably explained by absorption of toxins from the 
extensive abscesses with consequent damage to the other organs. 
Nevertheless, the most gratifying results are frequently obtained 
among patients in this group, who before their operation are often 
in extremely poor general condition and afterward become quite nor- 
mal. Group 4 is in reality a group by itself. It is composed of 
patients in whom nature has occluded the ureter, performing a so- 
called autonephrectomy, and the tuberculous process is supposed to 
have run its course. In only a few such cases was there any evidence 
of active tuberculosis in the kidneys; in the majority, the original 
kidney tissue had undergone caseation. The low mortality is evi- 
denced by the patient's high resisting powers. 



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SURGICAL RENAL TUBERCULOSIS 



215 



Table 10. 


— Duration op Preoperative Symptoms 






' Cases 


Not changed or 
slightly im- 
proved 


Per 
cent 


Markedly im- 
proved or 
practically 
well 


Per * Dead Per . 
cent *"»•** i cen t 


2 to 3 months ' 30 

4 to 12 months 162 

I to 5 years 155 

5 years 57 

Indefinite 31 

ToUl 435 


4 

S3 

40 

23 

4 

104 


13.3 
20.3 
25.8 
40.3 
12.9 
23.9 


18 , 60.0 
87 53.7 
71 j 45.8 
27 47.3 
23 74.1 
226 51.7 


8 

42 

44 

7 

4 

105 


26.6 
25.9 
28.3 
12.2 
12.9 
24.1 



The influence of the duration of preoperative symptoms on the 
prognosis might be considered from three phases: (1) Its relation to 
the severity of the bladder infection; (2) the time elapsing before post- 
operative improvement; and (3) the postoperative mortality. 

Although the severity of the bladder infection is largely dependent 
on the length of the preoperative symptoms there are other influential 
factors. It is not uncommon to observe marked inflammation and 
ulceration with symptoms of only a few weeks' duration. On the 
other hand, a fairly normal bladder is occasionally found when the 
disease has evidently existed many months. Further, with occluded 
renal tuberculosis when the initial symptoms had occurred and ceased 
several years before, the cause of the bladder infection having been 
removed by autonephrectomy, the bladder usually became fairly 
normal. 

In the majority of cases the duration of vesical symptoms persisting 
after operation diminished in direct proportion to the length of pre- 
operative symptoms. Of the patients with preoperative symptoms 
of less than three or four months' duration improvement was noted 
immediately in 48 per cent. When the symptoms existed a year or 
more prior to operation immediate improvement was noted in only 
15 per cent. 

A review of the mortality records shows that there is surprisingly 
little difference in the mortality with regard to the length of preopera- 
tive symptoms of less than five years. It has been claimed that the 
mortality of patients with short duration of symptoms is considerably 
higher than that of patients with long duration, and that a relative 
degree of immunity is established among the latter. This, however, 
was not borne out in our cases, since the group of patients with symp- 
toms of less than three months had practically the same mortality as 



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216 W. F. BRAASCH 

the group in which the symptoms were of much longer duration. 
It is of interest that the mortality in the group of patients having 
symptoms more than five years is considerably less than the average. 
This is explained by the fact that many of these patients had either an 
occluded renal tuberculosis or a high degree of immunity. This 
group also included 5 patients who had no evidence of disease other 
than albuminuria and slight pyuria, and in whom the discovery of 
renal tuberculosis was largely accidental. 



Table 11. — Bilateral Renal Tuberculosis 

Patients with definite bilateral involvement 16 

Patients reported dead (none alive longer than one and one-half 

years 18 

Patients living (less than two years after operation) 3 



It has been claimed that in cases of bilateral renal tuberculosis if 
the more diseased kidney is removed the patient will often improve, 
and in certain instances recover. It has also been claimed that in- 
fection in the remaining kidney may be reduced or overcome by com- 
pensatory hypertrophy; this has not, however, been substantiated 
by the end results in our series of bilateral cases. Thirteen of the 
16 patients with proved bilateral renal tuberculosis are reported dead; 
3 are living. None of the 13 patients lived more than one and one-half 
years after operation, and all but 3 died in less than six months. The 
3 patients living were operated on two years before their last report. 
One of these became steadily worse and recently had complicating 
perineal fistulas. The general health of the other two has temporarily 
improved. Both patients had a large active tuberculous pyonephrosis 
on one side, which was removed, and a fair degree of function in the 
other kidney. Such patients improve because the toxemia of acute 
infection is removed, and not because of improvement in the other 
kidney. When an occluded caseated kidney was removed, little or 
no benefit followed. Unless one kidney is largely destroyed and the 
other is in fair condition, operation should not be considered; and 
then only when infection, pain, or possibly hemorrhage renders it im- 
perative. Many cases of bilateral renal tuberculosis in which cure by 
operation was reported in the literature were probably not bilateral. 
Doubtless pus or tuberculosis bacilli picked up by the ureteral catheter 



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SURGICAL RENAL TUBERCULOSIS 217 

from an infected lower ureter, while the kidney itself was normal, could 
best explain such results. 

Table 12. — Mortality 

Per cent 

Operations for unilateral renal tuberculosis 516 

Operative mortality 7 l.S 

Patients with complete postoperative data 433 

Deaths 105 24 . 1 

One year or less after operation 58 55 .2 

Two years after operation 8 

Three years after operation 6 

Four years after operation 2 

Five years after operation 7 

Six years after operation 5 

Seven years after operation 3 

Eight years after operation 1 

Nine years after operation 1 

Ten years and more after operation 1 

Date of deaths not given 13 

The operative mortality (1.3 per cent) is a comparatively negligible 
factor. The total mortality (excluding bilateral renal tuberculosis) 
is 24 per cent, which includes every death from any cause following 
operation, some occurring as long as ten or more years afterward. 

Fifty -eight patients (55 per cent) died within one year after opera- 
tion. The relatively high mortality during the first year after opera- 
tion has been previously noted by several observers. It would seem 
logical to regard the early death as an evidence of the virulence of the 
infection rather than as a result of the operation. It may be inferred 
that the probability of death from tuberculosis decreases inversely 
with the length of time after operation. Owing to the inability to get 
accurate data as to the cause of postoperative death, no attempt was 
made to investigate this factor. 

Many patients died from diseases other than tuberculosis and from 
accidents, so that the late mortality from tuberculosis is really much 
less than our figures indicate. Furthermore, a considerable proportion 
of the total number of deaths reported occurred more than five years 
after operation. It would be conservative and more accurate, there- 
fore, to regard the actual late mortality as not more than 20 per cent. 

One hundred four (23 per cent) of the living patients stated that 
they had not entirely recovered from their bladder symptoms. From 
many of these answers to inquiries were received in less than two 



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218 W. F. BRAASCH 

years after operation, and it is safe to assume that at least 5 per cent 
would eventually report recovery from their symptoms. Moreover, 
64 patients reported a gain in weight and general condition, so that 
except for the bladder symptoms they were in a fairly good state of 
health. 

It may be assumed, therefore, that approximately 80 per cent of 
the patients will recover following operation for renal tuberculosis 
and that a complete cure, including cessation of urinary symptoms, 
may be expected in fully 60 per cent. 

CONCLUSIONS 

1. Renal tuberculosis occurs most frequently between the ages of 
20 and 40 (70 per cent). 

2. It occurs in the male almost twice as often as in the female. 

3. The postoperative mortality in the male patient is somewhat 
higher than in the female. 

4. The condition is usually not surgical in children; it occurs more 
often as a part of a general tuberculosis. 

5. Evidence of tuberculosis in other tissues of the body may be 
found in fully 71 per cent of the patients, if not in all. 

6. The postoperative mortality among patients with coincident 
lesions is not higher than that of the general average. 

7. Multiple lesions, unless they are a part of an acute general 
infection, do not necessarily render the prognosis more unfavorable. 

8. Evidence of healed pulmonary tuberculosis is present in fully 
one-third of the patients. 

9. The percentage of recovery among patients with healed pul- 
monary tuberculosis is above the average and may be considered 
indicative of increased powers of resistance. 

10. Coincident active pulmonary tuberculosis was found in ap- 
proximately 5 per cent of the patients, of whom more than 60 per 
cent recovered following nephrectomy. 

11. Involvement of genitalia is present in at least 73 per cent of 
male patients and does not seem to affect the ultimate recovery. 

12. Frequency of spontaneous healing of lesions in the prostate 
and seminal vesicles contra-indicates their removal by subsequent 
operation. 

13. Evidence of tuberculosis involving the bones and joints was 



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SURGICAL HENAL TUBERCULOSIS 219 

noted in 6 per cent of the cases; one-half of the lesions were active. 
The late mortality was 5 per cent, from which it may be inferred that 
the presence of such complications may be an index of increased 
resistance. 

14. Spondylitis, usually healed, was present in 5.7 per cent, with 
a mortality of 12 per cent. 

15. Chronic spondylitis does not influence the prognosis. Active 
spondylitis, although it does not contra-indicate nephrectomy, will 
not offer a favorable prognosis. 

16. Tuberculous adenitis was present in 19 patients (6.4 per cent) 
and the low mortality (10 per cent) is suggestive of a heightened 
resistance. 

17. Reduction in hemoglobin does not necessarily affect the 
prognosis. 

18. The mortality among patients with marked bladder involve- 
ment is twice as great as with slight involvement. The degree of 
involvement is dependent not so much on the duration of symptoms 
as on the virulence of the infection. 

19. The mortality percentage is markedly influenced by the degree 
of pathologic involvement of the kidney, increasing in proportion 
to the extent of the lesion. Early lesions have the lowest mortality 
and pyonephrosis the highest. 

20. Occluded renal tuberculosis is indicative of relative immunity 
and a low mortality. 

21. The duration of preoperative symptoms does not materially 
affect the late mortality. 

22. Recovery from bladder symptoms is more apt to occur, and 
earlier, when the preoperative symptoms are short than when they 
are long. 

23. Recovery or permanent improvement of the remaining kidney 
will not follow after one kidneyhas been removed in cases of bilateral 
renal tuberculosis. 

24. Operation in cases of bilateral renal tuberculosis is advisable 
only when there are acute unilateral complications, and then with no 
hope of eventual recovery. 

25. Late mortality is much the highest during the first year; it 
decreases with the length of time elapsing after operation. 

26. The operative mortality is a negligible factor; the late mortality 
(five years or less after operation) is approximately 20 per cent; 



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220 W. F. BRAASCH 

failure to effect complete cure is approximately 20 per cent; this 
leaves a prognosis of recovery iu 80 per cent and of a complete cure to 
be expected in fully 60 per cent of patients. 

BIBLIOGRAPHY 

1. Braasch, \V. F.: Cl*'nical observations from 203 patients operated on for renal 
tuberculosis. Jour. Am. Med. Assn., 1912, lviii, 397-401. 



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PAPILLARY TUMORS OF THE PELVIS OF THE 

KIDNEY* 

E. S. JTJDD 



Papillary tumors are seldom found in the pelvis of the kidney or in 
the ureters, although they are common among lesions of the bladder. 
Israel reported only 2 cases of papilloma of the pelvis of the kidney 
among 68 cases of renal tumors. Watson and Cunningham found 
only one such lesion diagnosed among 94 cases of renal and 
perirenal tumors collected at the Boston hospitals during a period of 
ten years. Albarran found 42 cases of pelvic renal tumor reported in 
the literature up to 1900. Eighteen of these were papillomas; 6 had 
invaded the ureter; 4 of the 6 extended also to the bladder. Suter 
reports having found a solitary papilloma in the lower end of one 
ureter which had caused very profuse hemorrhages. The kidney 
and bladder were explored, but bleeding from the ureter continued after 
the kidney was removed; the lesion was not discovered until the ureter 
was removed. Battle describes a case of calculus in the kidney and 
papilloma in the renal pelvis. After the extraction of the stone and 
conservative removal of the tumor, the growth recurred, and a nephrec- 
tomy was performed. Lower reports a case of malignant papilloma 
of the pelvis of the kidney with transplantation into the ureter and 
Madder, which is apparently very similar to the case I shall report. 

The genesis of papilloma of the kidney is not clear. Stones occur 
in the pelvis of the kidney in about 15 per cent of the cases, and these 
have been suggested as a possible etiologic factor. The papillary 
structure is regarded as proliferating epithelium of the renal pelvis, 
and the exact nature of the tumor seems to be based on the appearance 
of the epithelial cells within the connective tissue beneath the tumor. 
The presence of these cells as a distinguishing feature has been 
questioned by those who contend that epithelial cells are normally 
present ia the form of glands in this tissue. Morogna recently reported 

* Presented before the Minnesota Academy of Medicine, February, 1919. 
Reprinted from Journal-Lancet, 1919, xxxix, 247-253. 

221 



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222 



E. S. JUDD 



2 cases of renal pelvic tumor, and gave a detailed study of the his- 
tology with a very complete review of the possible etiologic factors 




Mucosa, of 

aixd 

aretei: 



<g *X 




Fig. 100 (212016). — a. Kidney with pelvis and upper segment of ureter. The 
incision has been made in the pelvis and the papillomas forced outward, b. Lower 
end of ureter with multiple papillomas, which probably extend downward into the 
bladder. 

suggested by other authors and by himself. He believes that it is 
possible, though not demonstrable, since thus far it has not been 



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PAPILLARY TUMORS OF THE PELVIS OF THE KIDNEY 



223 



proved that the tumors develop by metaplastic evolution; that the 
formation of papillomas of the renal pelvis may be explained by the 
occurrence of aberrant ectodermal inclusions during the period of 
development, excited to proliferation by an inflammatory process. 

Papillary tumors of the pelvis of the kidney are unlike the papillary 
adenomas that occur in the parenchyma of the kidney, as the pelvic 




FK. 101 (212016). 



-The open kidney and the exposed papillomas rising from the 
mucous membrane of the pelvis. 



tumor does not invade the kidney substance at any point; its growth 
and extension is in the pelvis itself, and it has a tendency to pass down 
the ureter. The papillary adenomas originate from the epithelial 
cells of the parenchyma, while the squamous-cell papillomas start 
from the epithelium of the pelvis of the kidney. The latter may be 
compared with the intracanalicular papillomas that occur in the 
ducts of the mammary gland, while the former may be compared 



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£24 £. S. JUDD 

with the cystadenomas that occur in the breast. Papillary tumors 
of the pelvis of the kidney are usually, if not always, multiple. These 
neoplasms may be divided into three classes: (1) the simple papillomas 
which show throughout their entire development and evolution the 
characteristics of all such tumors; (£) the epithelial papillomas which 
almost immediately show the characteristics of malignancy; and 
(3) those tumors which apparently change from a supposedly benign 
to a malignant growth. The same question arises with regard to the 
features distinguishing these benign and malignant papillomas as 
arises with regard to papillomas of the bladder. For practical pur- 




Fig. 102 (212016). — Photograph of papillary squamous-cell tumor of the pelvis of the 

kidney (closed). 

poses it would seem best to credit malignant tendencies to all of these 
papillomas, and treat them in a more or less radical manner. 

The particular case of squamous-cell papillary tumor of the renal 
pelvis which I shall report occurred in a priest aged 55. In nearly all 
of the reported cases the condition has occurred in men past 45. This 
patient consulted us in October, 1917. His chief complaint was 
hematuria. He had considered himself well until January, 1917, 
at which time he first noticed blood in the urine. The amount of 
blood was not great at any time, although it had persisted continuously 
since he first noticed it. He had no pain nor irritability of the bladder. 



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PAPILLARY TUMOBS OF THE PELVIS OF THE KIDNEY 225 

and there had been no difficulty in voiding, but there was some trouble 
in retaining the urine. He mentioned having a slight frequency of 
urinat'on, which caused him to get up once or twice at night. Two 
or three cystoscopic examinations had been made elsewhere, and the 
patient had been told that the left ureter was obstructed, that the 
blood in the urine was coming from the left side, and that the left 
kidney was functionally impaired. 

In reviewing the records of this case of papillary tumor of the 
pelvis of the kidney, I also briefly reviewed our records of other tumors 
of the kidnev. While Case 1 was found to be the only instance of 




Fig. 103 (212016). — Kidney shown in Figure 102, with pelvis open. 

definite papilloma of the kidney and ureter in the entire series of 
$07 eases of tumor of the kidney, in one other case (Case 2) the 
tumor had so completely destroyed the kidney that it was difficult to 
determine just w r here the lesion had originated. Dr. Broders, who 
made a histologic study of the cases in this series, believes that the 
second case should also be classified as a squamous-cell papillary 
tumor of the pelvis of the kidney. The statistics in the literature 
and those in our own records emphasize the fact that papillary tumors 
of the pelvis of the kidney are rare forms of renal tumors. They 
should, nevertheless, be borne in mind in the examination of such 

'l^-lo 



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226 E. 8. JUDD 

cases, particularly when a papilloma presents itself at the ureteral 
meatus.* 

Case 1 (212016). — The patient was large and obese. A specimen 
of urine showed considerable blood. An estimate of the kidney 
function showed a 40 per cent, phenolsulphonephthalein output in 
two hours, and 22 mg. of blood urea to 100 c.c. All the urine came 
from the right side. A diagnosis was made of surgical left kidney 
containing a tumor, or of a polycystic condition. 




Fig. 104 (212016). — Photograph of squamous-cell papillary tumor of the ureter (closed) . 

Operation, Nov. 7, 1917: A left anterior abdominal incision was 

made for the purpose of general exploration, but this revealed nothing 

of a pathologic nature in the abdomen. The right kidney seemed 

normal. A tumor could be palpated in the pelvis of the left kidney. 

The abdominal incision was extended laterally, and the left kidney and 

4 inches of the left ureter removed. The kidney proved to be about 

normal in size, except that the pelvis and the upper end of the ureter 

were much dilated. The pelvis of the kidney was about 4 inches in 

length and more than 2 inches in depth and breadth. A soft tumor 

could readily be palpated in the dilated pelvis and ureter. The 

* Since this paper was written, Dr. C. H. Mayo has operated in a similar case of 
squamous-cell papillary tumor of the kidney. A papilloma was found presenting at 
the left ureteral meatus. The growth was rather small, and responded to fulguration 
treatment. The patient was kept under observation for about three weeks. His 
bladder appeared to be entirely healed, when he had a severe attack of bleeding; the 
blood came from the ureter in the area in which the papilloma had been fulgurated. 
A functional test of the kidneys showed this particular kidney to be almost without 
function; the work was being done by the other kidney. The left kidney and ureter 
were removed, revealing a definite papillary tumor of the pelvis of the kidney with 
involvement of the ureter. This case is of particular interest because of the fact that 
the patient was only thirty-four years of age, and came to the Clinic with a diagnosis 
of tumor of the bladder, a condition naturally accountable for all his symptoms. The 
tumor of the kidney was not discovered until after the condition of the bladder had 
entirely cleared up. 



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PAPILLARY TUMORS OF THE PELVIS OF THE KIDNEY 227 

dilatation in the ureter extended down more than 2 inches, and then 
the ureter abruptly became normal in size and appearance. A 
nephrectomy was done, and the diseased portion of the ureter, with 
more than 2 inches of normal ureter, was removed; the distal end was 
ligated and allowed to drop back into the wound. On opening the 
kidney pelvis and the ureter, a large papilloma was found. The cap- 
sule, cortex, and parenchyma of the kidney appeared to be in good 
condition. Papillary projections of the tumor extended into the 
dilated calices; they originated from the mucous membrane of the 
pelvis of the kidney and the upper ureter. The tumor was identical 




Fio. 105 (212016). — Photomicrograph of squamous-cell papillary tumor of the pelvis 

of the kidney. 

in appearance with the papillomas of the bladder that are so common. 
(Figs. 100 to 106.) 

Histologic examination: The growth was diagnosed as a malignant 
papilloma. The neoplasm was made up of a proliferation of squamous 
epithelial cells on fine connective-tissue pedicles. In places the 
epithelium seemed to break through into the connective tissue, 
and show definite malignant tendencies. A large part of the mucous 
membrane of the pelvis of the kidney was normal. The tumors were 
on small pedicles and made a mass of considerable size. 

The patient made a satisfactory recovery after the operation, and 
was dismissed in a short time with his wound entirely healed. He 



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228 E. S. JUDD 

returned to his duties, and remained well for about nine months. 
In August, 1918, he again had trouble and passed a rather large amount 
of blood in the urine during one urination only. He had no further 
trouble for three months, when he again began to pass blood and blood 
clots. This was repeated several times prior to his second examina- 
tion; the urine always cleared up again, and the patient was well. 
When he presented himself a second time, the urinalysis was negative 
with the exception of a few blood cells. Cystoscopic examination 
showed a cauliflower papillary growth at the site of the left meatus 
about three-fourths of an inch in diameter. The growth extended 
almost to the meatus of the urethra; an entirely separate growth was 
noticed in the trigone. 




Fig. 106 (212016). — Squamous-cell papillary' tumor shown in Figure 104. ureter open. 

Jan. 3, 1919, a second operation was performed. A large extra- 
peritoneal opening was made in the dome of the bladder, and the 
papillomas were seen bulging from the left ureteral meatus. There 
was also a separate papilloma, apparently a graft, on the base of the 
bladder close to the urethra. The tissues in the left prevesical space 
were separated, and the left ureter, which was several times the normal 
size and had the feel of a hard cord, was exposed. This was dissected 
free, and removed en masse from the point at which it had previously 
been ligated, down to and including the extension into the bladder. 
A piece of tissue about 4 cm. in diameter and the entire thickness 
of the bladder was removed; the small papilloma in the base of the 
bladder was also excised. The bladder and prevesical space were 



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PAPILLARY TUMORS OF THE PELVIS OF THE KIDNEY 



229 



drained separately. Convalescence was satisfactory, and the wound 
healed promptly. 

Examination of the specimen showed that the ureter was about 1 .5 
era. in diameter, and that the walls were greatly thickened and in- 
filtrated. The growth at the ureteral meatus seemed to extend on to 
the bladder mucosa so that the greater part of the tumor seen in the 
bladder was made up of multiple papillomas prolapsing from the ureter. 
On opening the ureter it was seen to be almost completely filled with a 
great many separate papillomas, extending all along the mucosa from 
the point of the former ligation to and including the bladder mucosa. 
These tumors were identical, both grossly and microscopically, with 




Fio. 107 (235849). — Photomicrograph of squamous-eell papi'lary tumor of the kidney. 
The tumor is made up of squamous-cell and slender intervening fibrous stalks. 

those removed from the kidney and the ureter more than one year 
before. The solitary papilloma of the bladder mucosa was of the 
same structure as those in the kidney and ureter. 

The patient is well at the present time, but it is too soon to offer 
an opinion as to whether or not he will have further trouble. We have 
advised examinations of the bladder every few months for a period of 
two years. 

Case 2 (235849). — A man, aged 49, came for examination com- 
plaining of pain in the right lumbar region. For a number of years 
he had had a great deal of pain in his back, but this pain had disappeared 
about eight years before and he had been free from it until one month 



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230 E. S. JUDD 

before when it appeared in the right lumbar region. He urinated from 
three to four times at night, and every two or three hours during the 
day. His normal weight was 212 pounds; he now weighed 169. 

Examination revealed a large tumor in the right kidney region. 
The hemoglobin was 56 per cent; leukocytes, 31,800. The urine 
contained pus and red blood cells. X-ray examination showed 
multiple shadows in the right-kidney region. A diagnosis of right 
calcareous pyonephrosis was made. Fifty-five per cent phenol- 




Fig. 108 (103235). — Photograph of papillary adenomatous tumor of the parenchyma 

of the kidney. 

sulphonephthalein was passed in two hours; the function of the right 
kidney was about half that of the left. 

On July 5, 1918, the patient was operated on. The kidney, con- 
taining two stones and weighing 950 gms. was removed. Examination 
of the specimen showed almost complete destruction of the kidney, 
a papillary carcinoma 8 cm. in diameter, nephrolithiasis, and three 
stones in the mass. The patient died on the tenth day after the 
operation. At necropsy metastatic malignancy in the mediastinal 
lymph glands and also in the lungs was found. The malignancy 
of the glands was of the type found in the kidney. 



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PAPILLARY TUMORS OF THE PELVIS OF THE KIDNEY 231 

Histologically, the tumor was of the squamous-cell papillary type, 
which probably originated in the pelvis of the kidney; however, 
this could not be definitely determined because the destruction of 
the tissue was so advanced. The ureter was not involved (Fig. 107). 

In addition to Cases 1 and 2 there were three in which papillary 
tumors originated in the parenchyma of the kidney. In two it seemed 
probable that the tumors were secondary to cysts. In all three the 
growths were so extensive and destructive that it was difficult to be 
certain of their exact nature; however, in the light of more careful 
study they appeared to be papillary adenomas. 



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Fig. 109 (103235). — Photomicrograph, of tumor shown in Figure 108. 

Fifty-one of the series of 207 cases were of benign tumor, and 34 of 
these were cysts. One hundred fifty-six cases were of malignant 
tumor, and 113 of these were classified hypernephromas, 22 carcino- 
mas, and 15 sarcomas. 

ABSTRACTS OF HISTORIES OF THREE CASES OF PAPILLARY ADENO- 
MATOUS TUMOR OF THE KIDNEY 

Case 3 (34504). — A man, aged 47, had been subject to attacks of 
colicky pain for from twenty to thirty years. The pain began in the 
right loin and extended downward. Blood and pus had been noted 
in the urine. The attacks appeared at intervals of from a few months 
to four years. Between attacks the patient was well. During the 



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232 



E. S. JUDD 



past two years the pain had been more frequent, and in the past year 
it was almost constant, especially at night. There was blood in the 
urine most of the time. The patient had lost weight for several 
months, and was 40 pounds under weight. 

At the time of our examination the patient was somewhat anemic 
and emaciated. The hemoglobin was 70 per cent. Several small 
shadows in the right-kidney area were seen in the roentgenogram, 




Fi«3. 110 (141532). — Photomicrograph of papillary adenomatous tumor of the 
parenchyma of the kidney. The tumor is made up of columnar cells with intervening 
fibrous stalks. 

and a mass which was supposed to be an enlarged kidney could be 
palpated. Blood and pus were found in the urine, although the 
amount of blood was not sufficient to be suggestive of a tumor. A 
diagnosis of right pyonephrosis with stones and a normal left kidney 
was made. 

At operation, March 1, 1910, the enlargement proved to be due 
to a malignant papillary adenoma of the pelvis of the kidney. The 
tumor was rather large; stones were present in the pelvis. The patient 



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PAPILLARY TUMORS OF THE PELVI8 OF THE KIDNEY 233 

made a good immediate recovery from the operation. He died sud- 
denly in July of the same year. 

Case 4 (103235). — A man, aged 29, came for examination com- 
plaining of hematuria. Eight years before, following heavy lifting, 
he had had severe pain for five or six hours, which extended from the 
right testicle along the right abdomen. Clots of blood were passed; 
this recurred for a few hours three or four times a year. The patient 
had had only two attacks of colic, the last one four years before his 
visit to the clinic. He had had no frequency, urgency, nor burning, 
but some pain about the neck of the bladder when the clots passed. 

The functional test of the kidneys showed a phenols ulphonephtha- 
lein return in fifteen minutes, 56 per cent in two hours. A slight 
amount of albumin, some pus, and red blood cells were found in the 
urine. Cystoscopic examination showed urine spurting normally 
from the right meatus, but there was some question as to whether 
it was absolutely free from blood. The hemoglobin was 84 per cent. 
A diagnosis of a surgical right kidney was made. The patient went 
home presumably to arrange his affairs and return for an operation, 
but he waited three months, at the end of which time he was weak 
and emaciated, and his hemoglobin had dropped to 44 per cent. 
Blood had been present in his urine except for short intervals. At 
operation, July 28, 1914, a small carcinomatous papillary cyst adenoma 
of the right kidney was found, and the kidney was removed. The 
renal artery resembled a pipe stem, and very marked hardening of 
its tissues was noted. The patient made a good immediate recovery, 
and was discharged in good condition. (Figs. 108 and 109.) 

Case 5 (141532). — A woman, aged 45, came for examination 
because of "kidney trouble." Her appendix and one ovary had been 
removed. At intervals during the previous three years she had had 
hematuria of varying degrees, and had passed clots and also bright 
red blood. During the last attack, one month before, she passed a 
teacupful of bright-red blood, and at the same time experienced 
colicky pain in the right-kidney area. She voided two or three times 
at night, and had lost 10 pounds in weight in a year. 

Examination showed pus and blood in the urine, and an indefinite 
enlargement in the upper pole of the right kidney. The hemoglobin 
was 82 per cent. The functional test showed that 20 per cent phenol- 
sulphonephthalein passed in two hours, and just a trace of blood and 
no urine coming from the right side. A diagnosis of tumor of the 



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234 E. S. JUDD 

right kidney was made. At operation, Sept. 28, 1918, the kidney and 
adrenal gland were removed. The tumor was found to be a carcino- 
matous papillary cystadenoma. Complete suppression occurred 
after the operation, and the patient died about the tenth day. 
Necropsy showed no other evidence of malignancy, although it 
revealed a marked nephritis in the remaining kidney, a cholecystitis 
and cholelithiasis, and a hemorrhagic colitis. (Fig. 110.) 

SUMMARY OF CASE HISTORIES 

A brief review of the histories of these 3 cases of papillary adeno- 
matous tumor would seem to indicate that pain in the region of the 
affected kidney, extending into the loin, is a common accompani- 
ment of renal adenoma, and that patients thus afflicted quickly 
show emaciation. A palpable tumor was present in all the cases. 
Blood in the urine is a common symptom in cases of malignant tumor 
of the kidney, except sarcoma, which occurs almost altogether in 
children. Blood coming from one kidney should suggest tumor of the 
kidney. In this connection it is necessary to keep in mind the pos- 
sibility of tuberculosis, and also those unexplained cases of essential 
hematuria. The bleeding in our case of papillary tumor of the pelvis 
of the kidney was different from that which occurred in the three 
cases of papillary adenomatous tumors. In the first case it occurred 
in hemorrhages, and the urine was otherwise clean. In the cases 
of papillary adenomatous tumor a great deal of blood and pus in 
the urine was a constant finding. The x-ray shadows showed stone, 
and this led us to think that pyonephrosis and calculi might be 
present. One point discussed by Cumston in the differential diagnosis 
is that finding a hematonephrosis in a case in which hemorrhages had 
been the chief symptom would suggest the presence of a pelvic 
papilloma. This writer inferred that the papilloma would at times 
obstruct the ureter, and thus cause a hydronephrosis. It seems to me 
that a colloidal silver plate made of the pelvis of the kidney in a case 
of renal papilloma might be quite suggestive, and possibly with the 
plate a diagnosis could be made; at least a cystogram made of the 
bladder in which a papilloma exists usually gives a characteristic 
picture. In our examination, and especially in the treatment of these 
cases, we must bear in mind the possibility of the existence of a papil- 
loma in the ureter alone which will produce these same symptoms. 
This lesion is very rare; only a few cases are on record. 



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TREATMENT 

Nephrectomy is the treatment indicated in cases of squamous-cell 
papillomas and papillary adenomatous tumors of the kidney if the 
opposite kidney is in good condition. Conservative treatment of 
such tumors is almost conclusive evidence that they will recur else- 
where, and it should also be taken into consideration that there is a 
possibility of an immediate change from a benign to a malignant growth. 
It would seem almost unnecessary to remove the ureter with the 
kidney in cases of renal papillary adenomatous tumors when there is 
no apparent extension into the ureter, but our experience with this 
one case of squamous-cell papilloma of the pelvis certainly indicates 
the advisability of always removing the entire ureter down to the 
wall of the bladder at the time of the nephrectomy, or at a second- 
stage operation very soon afterward. The most probable point at 
which broken-ofT pieces of squamous-cell papillary tumor of the kidney 
find lodgment is just at the ureterovesical juncture; therefore the 
best means of cure is to remove the entire ureter. 

BIBLIOGRAPHY 

1. Albarran, quoted by Pels-Leusden, F. : Ueber pap ill are Tumoren des Nieren- 
beckeos in kiinischer und pathologisch-anatomischer Hinsicht. Arch. f. klin. Chir., 
1902, Irviii, 687-714. 

2. Battle, W. H. : A case of calculus in the kidney, associated with a papilloma in the 
reaal pelvis; nephrotomy; nephrectomy: recovery. Tr. Clin. Soc. Lond., 1895, xxviii, 
235-239. 

3. Cumston: Neoplasms of the renal pelvis and ureter, with the report of a case. 
Am. Jour. Urol., 1918, ix, 21-26. 

4. Israel: Quoted by Morogna. 

5. Lower, W. £.: Neoplasms of the renal pelvis with especial reference to trans- 
plantation in the ureter and bladder. Surg., Gynec. and Obst., 1914, xviii, 151-158. 

6. Morogna, P.: Contributo alio studio dei papillomi del bacinetto. Policlinico. 
1914, xxi, sex. chir. 377-391. 

7. Suter, F. : Primary ureter-papilloma. Nephro-ureterectomy. Recovery. Urol. 
ud Cutan. Rev., 1913, i, 62-65. 

8. Watson, F. S. and Cunningham, J. H.: Diseases and surgery of the genito- 
urinary system. Philadelphia, Lea and Febiger, 1908, ii, 261. 



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SURGERY OF THE KIDNEY* 

E. S. JUDD 



The improvement and development of the surgery of the kidney 
have been brought about largely by a better understanding of the 
pathology, and more by the modern methods of clinical and labora- 
tory examination which have enabled us to determine more accurately 
than heretofore the existing condition. Very important changes have 
also been made in the surgical technic. 

Congenital anomalies. — Some of the congenital anomalies which 
affect the kidney may have a very important bearing on any surgical 
procedure. The horseshoe kidney occurs quite frequently, and in 
certain cases one half of it may be diseased and the other half normal. 
This condition will often be encountered without any previous knowl- 
edge of its presence, and the fact that the two kidneys are fused adds 
greatly to the difficulties of the removal of the diseased portion. It 
should also be remembered that one kidney may be imperfectly 
developed or that there may be a congenital absence of one kidney. 
These conditions especially call attention to the importance of deter- 
mining whether or not both kidneys are present and what their func- 
tional capacity is before any operation is undertaken. Should it be 
impossible to make sure at the time of the examination that both kid- 
neys are present and functioning, it may be necessary to explore both 
sides before deciding to remove the infected kidney. If one kidney 
is absent or not functioning, the remaining kidney will be twice its 
normal size. 

The kidney may be congenitally displaced, and if so it is usually 

found at a level with the promontory of the sacrum. This condition 

is known as pelvic or ectopic kidney and differs from the floating or 

movable kidney in that the renal vessels may arise from the common 

or internal iliac vessels and the pedicle of the kidney may be short 

* Presented before the Minnesota State Medical Association, Minneapolis, October, 
1919. 

Reprinted from Minn. Med., 1920, iii, 221-227. 

[236 



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SURGERY OF THE KIDNEY 237 

so that it is more or less fixed in the pelvis. A pelvic kidney may be 
normal in functionating capacity and cause no trouble, or it may be 
afflicted with any of the pathologic conditions which arise in a normal 
kidney. A kidney in the pelvis is of great importance from the stand- 
point of diagnosis. Several times an infected ectopic kidney on the right 
side has been approached on the presumption that the condition was an 
appendiceal abscess. It seems advisable to have a pyelogram made in 
all uncertain cases of pelvic tumor in which an ectopic kidney may 
be the tumor. In a series of 19 cases of pelvic kidney previously 
reported 9 of the patients required operation because the kidney was 
pathologic. In the other 10 cases, the kidney was apparently func- 
tioning normally. 

The movable and the floating kidney have ceased to occupy an 
important place in surgery. At one time the surgeon considered it 
advisable to fix in the normal position all kidneys that seemed to lie 
too low or to be too movable, but at the present time the mere position 
of these kidneys is not deemed an indication for operative treatment. 
Usually, this condition of general visceroptosis is associated with the 
syndrome of general neurasthenia and will not be benefited by surgery. 
Undoubtedly, at times the floating kidney assumes a position which 
causes a change in the position of the ureter, so that the flow of the 
urine is obstructed and an intermittent hydronephrosis, which can be 
determined by a special examination, results. In such cases surgical 
treatment is usually advised, although it does not always obtain the 
best results. Occasionally, it may seem advisable to fix a floating 
kidney to relieve symptoms produced by its abnormal position; 
but more often interference with function is the factor which decides 
whether or not operation should be done. 

Contusion and rupture of the kidney. — This injury may occur with- 
out any external evidence of trauma over the kidney area. The 
initial symptom is bloody urine and, if the injury is not extensive, this 
may subside without further trouble. If the hemorrhage is severe 
and continuous I believe it is advisable to explore early, in view of the 
fact that the lacerations may have extended through the pelvis or 
involved the ureter, and, as a result, the parenchyma will surely 
become infected, eventually destroying the kidney. In some of these 
cases, the injury to the vessels, ureter, and pelvis is undoubtedly not so 
great but that they could be repaired by an early operation which 
enables the kidney to functionate again. After the infection occurs 



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238 E. S. JUDD 

in a ruptured kidney the chance of saving it is slight. Nephrectomy 
will often have to be resorted to in cases of severe injury. 

Hydronephrosis. — If the escape of the urine from the kidney is 
suddenly and completely arrested by ligation of the ureter, the organ 
ceases to secrete, and finally undergoes atrophy. It might be expected 
that an unfavorable prognosis would follow ligation of the ureter and 
that eventually the kidney would have to be removed, but in not a 
single case of the many instances in which we have been obliged to 
ligate the ureter has a demonstrable hydronephrosis developed, and in 
no instance has it been necessary to remove the kidney. Experimental 
work on animals, and Caulk's operative work on the human have 
demonstrated that if the ureter is liberated after it has been ligated 
completely and has remained closed for as long as fourteen days, 
the kidney tissue will gradually recover and functionate normally. 
Hydronephrosis, then, will not result, from the ligation of the ureter, 
but it may and usually does result from hindrance to the flow of urine 
during a long period. The altered position of the kidney or the pres- 
sure of an anomalous vessel on the ureter may eventually result 
in a hydronephrosis. At first the hydronephrosis will be inter- 
mittent; later, after changes have occurred in the kidney tissue, 
especially in the pelvis, the hydronephrosis will become permanent. 
A small hydronephrosis, with some dilatation of the calices, is not un- 
common and may exist without producing symptoms. In view of the 
fact that surgery is not always satisfactory in these cases it seems best 
not to be too urgent in advising it. If an anomalous vessel is the 
cause, the condition will be relieved by the division of this vessel, 
provided the hydronephrotic sac is not too large. If the cause of the 
condition is a stricture or an angling of the ureter a plastic operation 
at this point of the ureter would seem to be indicated. A number 
of these plastic operations have been done in the clinic in cases in which 
hydronephrosis was sufficient to produce marked symptoms and yet 
had not resulted in any destruction of the kidney. The results in 
these cases have not been generally satisfactory. Some patients have 
had recurring trouble which required nephrectomy. The operation 
described by Peck, "splinting the ureter," has proved very satisfactory 
in some cases. If the hydronephrotic sac is large and the calices 
markedly dilated, it will be best to resort to a nephrectomy if the other 
kidney has been found to be normal. Undoubtedly these conditions 



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SURGERY OF THE KIDNEY 239 

are more than a mere dilatation or they would be entirely relieved by a 
plastic operation at the point of narrowing. 

Pyogenic infections.— Pyogenic infections of the kidney are common, 
and in most instances surgical treatment is indicated. If the infection 
takes the form of a pyelitis or a pyelonephritis, however, both kidneys 
are usually involved, and little can be accomplished by surgery. A 
common type of infection in the kidney occurs from several days to 
several weeks following attacks such as of tonsillitis and boils. The 
kidney receives the organism through the blood stream and the 
involvement occurs in the form of a single abscess or, more often, 
multiple cortical abscesses. This is indicated by chills, a rise in tem- 
perature, and a high leukocyte count, and usually by much local pain 
and tenderness, especially if the infection extends into the perinephritic 
space. A large perinephritic abscess sometimes forms, drainage of 
which is frequently sufficient. If multiple abscesses are found in the 
cortex with considerable destruction of the kidney substance, a 
nephrectomy is indicated. 

Pyonephrosis is that form of infection in the kidney in which sup- 
puration is combined with obstruction to the outflow of the urine. 
This condition may result from infection associated with hydro- 
nephrosis or with stones in the pelvis or renal tissue. Bilateral pyo- 
nephrosis is frequently encountered in cases of severe cystitis associated 
with prostatic enlargement and bladder stone. If the pyonephrosis 
is unilateral, nephrectomy is often advisable. In some cases in which 
the infection is not severe or in which there is some contra-indication 
to performing a nephrectomy the kidney pelvis and the kidney tissue 
may be drained, although under ordinary circumstances the establish- 
ment of drainage in an infected kidney is not altogether satisfactory. 
It is often difficult to decide just how to proceed in cases of bilateral 
pyonephrosis. Many of these cases are associated with stone forma- 
tion, and the phenolsulphonephthalein output may be low and the 
blood urea high. It seems to me that the most conservative method, 
the removal of stones from one kidney at a time, is best. In occasional 
cases a subcapsular nephrectomy will be required later because of 
remaining infection and persistent sinuses, but this can be done at a 
time when the better kidney has resumed good function. I believe 
that it is easier for the patient, even in the cases of non-infected bilat- 
eral nephrolithiasis, to have one side operated on at a time, the second 
operation to be performed as soon as complete convalescence has taken 



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240 E. S. JUDD 

place following the first. Stones in the kidney are most often formed 
in the pelvis or in one of the calices, although they may occur in the 
kidney tissue. Calcareous formations in the kidney are frequently 
multiple; they are ordinarily determined by x-ray examination, but 
even when the x-ray shows only a single shadow the possibility of a 
number of stones must be considered. I am convinced that the re- 
ported frequency with which kidney stone is found following operation 
is largely due to the fact that small stones are overlooked at the time 
of the operation. In operating it is always advisable to deliver the 
kidney from the wound in order to get good exposure. When it is 
possible the stone should be removed through an opening in the pelvis, 
although an incision into the cortex is better handled now than for- 
merly. It is always wise to make an opening in the pelvis large enough, 
to introduce a finger to explore the calices. This is the best method 
by which to find stones. It is surprising how large a stone in the 
kidney may escape notice if the pelvis is not opened and examined 
from the inside. It has been considered indiscreet to suture these 
openings in the pelvis or ureter but I believe that this can be done 
safely with fine, plain, quickly absorbable catgut; certainly the suture 
adds greatly to the convalescence as in many cases no urine will drain 
at any time. The contra-indication to closing the kidney pelvis or 
ureter is the severe infection which may exist. 

Tuberculosis of the kidney, — Tuberculosis of the kidney is a 
common finding. In every instance in our cases in which tuberculosis 
bacilli were found in the urine coming from the ureter, a definite 
tuberculous process was demonstrated in the kidney. It is of the 
greatest importance to recognize the condition while the process is 
confined to a single kidney. When only one kidney is involved, the 
ultimate results of its removal will be very good, but if the condition 
has reached the other kidney, no form of treatment is effective. Under 
ordinary circumstances, if one kidney is extensively involved and the 
other only slightly, the one showing the greatest destruction should be 
removed unless there is evidence that the disease is general. Un- 
doubtedly tuberculosis of the kidney is often secondary to tuberculosis 
of the lungs. A healed lesion in the lung, or a fairly inactive one, 
is not a contra-indication to removal of a kidney in which an active 
tuberculosis exists. It adds to the risk, but the operation offers the 
patient much more than any other treatment (Fig. 111). 

In the technic of the removal of a tuberculous kidney, the perirenal 



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SURGERY OF THE KIDNEY 



241 



fat must be removed completely and the cut end of the ureter isolated, 
or the entire wound may become infected and tuberculous with very 
serious results. Tubercles are found in the tissues of the ureter, 
and in many cases in the bladder. Removal of the entire ureter has 




Fro. 111. — Line of skin incision in kidney casea as previously suggested by W. J. 

Mayo. 

been advocated but this adds greatly to the extent of the wound and 
does not accomplish its purpose, since a ureter cut off at the bladder 
offers the same opportunity for soiling as it does when cut off at the 
kidney pelvis. To prevent infection from the cut end of the ureter 

19-16 



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242 



E. S. JUDD 



W. J. Mayo devised the plan of suturing the end of the ureter to the 
skin so that it prolapses out of the wound. Sometimes it is difficult 
to free the stiff ureter sufficiently to get it entirely out of the wound. 



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If this cannot be done the end of the ureter is freed for several inches 
and the ligated end is threaded into a rubber tube, which is allowed to 
project from the wound for at least six days. In this manner, any 
soiling from the cut end of the ureter is carried to the outside by the 



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SURGERY OF THE KIDNEY 



243 



tube and is not poured into the perirenal tissues. The results following 
these procedures of isolating the ureter after the nephrectomy fop 
tuberculosis of the kidney indicate their great importance (Figs. 112 
and 113). 

Tumors of the kidney. — A study of renal tumors shows benign 
tumors of the kidney to be very rare. Solitary cysts that may be 



Torcep readu to 
be wvtVuira.u/n, 
from tu,be 




Fig. 113. — Method of isolating cut off area of a tuberculous ureter. 

enucleated from the kidney are sometimes seen. Congenital, bilat- 
eral polycystic disease is more common, but it is not particularly 
amenable to surgical treatment. Patients are usually very anemic 
and have a low kidney function. If one of the cystic kidneys is also 
infected and the other is free from infection, it is sometimes advisable 



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244 



E. S. JUDD 



to remove the infected organ. Our experience with the Rovsinfg 
operation, which consists in collapsing the cysts in first one kidnejr 
and then the other, has not been entirely satisfactory. The common 
tumors of the kidney are malignant, either hypernephroma or carcin- 
oma in the adult, or sarcoma in children. The results of nephrectomy 
for hypernephroma have been more permanent than those of most 
operations for malignancy. The tumor develops slowly and, if 
operated on before it becomes fixed by attachments formed from 
extension, especially through the pedicle and extensive lymphatic 
involvement, the results are very satisfactory. If the tumor is large 
and fixed no operation should be attempted, and it may be well to 




Fig. 114. — Tuberculous ureter fastened in rubber tube isolating it from the surrounding 

tissues to prevent soiling. 

use radium. Some of our patients with inoperable tumors who other- 
wise were in fair condition have seemed to do very w r ell under this 
treatment. Operation for carcinoma and for sarcoma of the kidney 
in children is less favorable; while a very large tumor may be removed 
successfully it will usually recur early (Fig. 114). 

The technic of operation. — I wish to call your attention to the 
incision which we have found most useful in exposing the kidney. 
This was described by \V. J. Mayo some years ago (Fig. 111). 
It combines the advantages of the so-called posterior and anterior 
incisions, adding materially to the facility with which these operations 
may be performed. It is crescentic, beginning well forward on the 



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SURGERY OF THE KIDNEY 



245 



flank above the spine of the pubic bone, extending backward and up- 
ward to the point of articulation between the last rib and the vertebrae. 
The. incision must extend far enough forward to give a good exposure 
of the pedicle in cases in which the pedicle is short and the kidney 
high-lying. The operation is extraperitoneal throughout. The 
important sensory nerves come into view readily and are preserved. 
In some instances it is necessary to cut through the muscles. Second, 
the perirenal fat should be extensively removed in all tuberculous 
and malignant cases. Third, the cut-off end of the ureter should 
he isolated in all tuberculous cases in such a manner that it will not 
soil the wound. This may be accomplished by fastening the ureter 
outside the wound or isolating it by threading it through a rubber 
tube. Fourth, the pedicle consisting of the renal vessels should be 
caught by two clamps. When tying the pedicle the deeper of the 
two clamps is released while the ligature is being tightened onto the 
pedicle; in this way the pedicle is controlled by the ligature and 
by the second clamp. Another ligature is then placed on the pedicle 
before the second clamp is removed. 



Table 1. — Operations ox the Kidney in 1918 

Cases 

Perinephritic abscess — drainage 7 

Anomalous kidney — exploratory pelviotomy 1 

Carcinoma of the kidney — exploration 2 

Cysts of the kidney — exploration 1 

Cysts of the kidney — Rovsing operation 2 

Cystadenoma — enucleation 1 

Hematuria — nephrotomy 1 

Hydronephrosis and ureteral calculi — nephro-ureterec- 

tomy 1 

Hydronephrosis and hydro-ureter — nephro-ureterectomy 2 

Hydronephrosis (intermittent) — Peck's operation 2 

Plastic operation and division of blood vessels 4 

Hypernephroma — exploration 3 

Inoperable malignancy, tuberculosis, both kidneys dis- 
eased — exploration 12 

Movable kidney — decortication and nephrorrhaphy . ... 2 

Nephrolithiasis — nephrolithotomy and pelviolithotomy . 86 

Nephrectomy (partial) 6 

Edebohls' operation 2 

Pyonephrosis and pyo-ureter — nephro-ureterectomy 5 

Acute suppression — decortication 4 

Papillitis — nephrotomy 2 

Tuberculosis — nephro-ureterectomy 8 

Sinus dilatation and curettage 1 



Deaths 



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246 



E. S. JUDD 



The points to be emphasized in operations for the removal of stones 
from the kidney are, first, exposure of the kidney by displacing it from 
the wound; second, careful exploration of the kidney pelvis and calices 
with the finger in order to avoid overlooking any stones; and third, 
closure of the incision in the kidney pelvis in non-infected cases. 



Table St. — Operations on the Kidney in 1918 



Cases 



Nephrectomy , 

Tuberculosis of the kidney 

Pyonephrosis (associated with nephrolithiasis, 84) .... 
Hydronephrosis (associated with nephrolithiasis, 6) . . 
Tumor of the kidney 

Hypernephroma 

Carcinoma 

Sarcoma 

Pyelonephritis 

Polycystic kidney 

Nephrolithiasis with multiple cortical abscesses 

Multiple cysts and abscesses 

Remnant of kidney following operation elsewhere 

Congenital cystic kidney 

Retroperitoneal sarcoma adherent to kidney 

Multiple abscesses of the kidney 

Pyelitis 

Infected atrophic kidney 

Recurring stones with sand 

Ruptured kidney — perinephric abscess 

Branched stone with kidney substance destroyed .... 

Nephrolithiasis — chronic nephritis 

Chronic infection 



Deaths 
£39 



81 
67 
41 

18 
S 
1 
9 
S 
2 
2 
2 



SURGICAL MORTALITY 

Of the 239 patients on whom nephrectomy was done 7 (2.9 per 
cent) died. Three had tuberculosis of the kidney; one died of tubercu- 
lous bronchopneumonia, one of miliary tuberculosis of the lungs and 
tuberculous peritonitis, and one of chronic nephritis and bilateral 
pleuritis. Two of the patients had pyonephrosis; one died of hemor- 
rhage (forceps on pedicle) and one of thrombophlebitis of the inferior 
vena cava, the common, internal, and external iliac veins. One 
patient with hypernephroma died of an infection. This patient was 
operated by the transperitoneal route. One patient with carcinoma 
of the kidney died of acute nephritis and metastatic carcinoma in 
the lungs. 



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SURGERY OF THE KIDNEY 247 

BIBLIOGRAPHY 

1. Caulk, J. R. and Fisher, R. F.: Experimental study of the effect of ureteral 
ligation with particular reference to its occlusion during pelvic operation. A prelimi- 
nary report. Tr. Am. Assn. Genito-Urinary Surgeons, 1915, x, 72-81. 

2. Judd, £. S., and Harrington, S. W. : Ectopic or pelvic kidney. Surg., Gynec. 
andObst., 1919, xxviii, 446-451. 

3. Mayo, W. J. : The incision for lumbar exposure of the kidney. Ann. Surg., 1912, 
lv,«$-«5. 

4. Peck, C. H.: Ureteral obstruction. Tr. Am. Surg. Assn., 1915, xxxiii, 441-444. 

5. Rovsing, T.: The treatment of multilocular kidney cystoma (congenital cystic 
kidney) by means of multiple punctures (Translation). Am. Jour. Urol., 1912, viii, 
120-124. 



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DILATATION OF THE URETER AND RENAL- 
PELVIS* 

W. F. BRAASCH 



Dilatation of the ureter and renal pelvis may be caused by these 
etiologic factors: mechanical obstruction, infection, and disturbance 
of innervation. The various types may be recognized by differences 
in (1) outline, as observed in the pyelo-ureterogram, (2) pathology, 
and (3) clinical data. 

MECHANICAL OBSTRUCTION 

Continued mechanical obstruction in any portion of the urinary 
tract is necessarily followed by dilatation of the portion above it. 
It may be conceivable that an occasional obstruction may cause 
urinary retention of such short duration that no dilatation in the 
ureter or pelvis would be apparent; but in the presence of a more or 
less permanent obstruction causing urinary retention, it would be 
impossible not to have a visible permanent distention of the ureter 
and the renal pelvis. 

Pelvis. — Dilatation in the pelvis caused by mechanical obstruction 
is usually characterized by (1) predominance of dilatation in the 
pelvis rather than in the calices or ureter, and (2) comparative regular- 
ity of pelvic outline. 

The various changes in the pelvic outline resulting from mechanical 
obstruction are best described by considering them according to degree. 
As demonstrated by the pyelogram, the following deviations from the 
normal pelvic outline may be noted: 

1. Early hydronephrosis: (a) flattening of terminal irregularities; 
(b) broadening of the base of the calix; (c) increase in size of the true 
pelvis, and (rf) shortening of papillae. 

2. Moderate hydronephrosis: (a) broadening of the entire calix; 

(b) shortening of papillae; (c) change in the angle of insertion of the 

* Chairman's Address, presented before the Section on Urology at the Seventieth 
Annual Session of the American Medical Association, Atlantic City, June, 1919 
Reprinted from Jour. Am. Med. Assn., 1919, lxxiii, 731-737. 

248 



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DILATATION OF THE URETER AND RENAL PELVIS 249 

ureter; (d) increase in size of the pelvis, and (e) changes of secondary 
infection. 

3. Large hydronephrosis: (a) partially filled calices; (b) rounded 
individual areas; (c) single calices; (d) diffuse outline of rounded sac, 
and (f) dim areas suggestive of diluted opaque fluid. 

Early hydronephrosis. — Probably the first deviation from the 
normal to be noted in the pyelogram with early hydronephrosis is a 
flattening of the terminal irregularities of the normal minor calices, 
together with a slight broadening of the major calix. Immediately 
following or accompanying these changes may be noted an increase 
in the size of the true pelvis. With the increase in the size of the 
pelvis, a shortening or flattening of the papillae projecting between 
the major calices may be noted. 

Moderate hydronephrosis. — With further increase in size of the 
hydronephrosis, the major calix becomes considerably broader in 
its entire extent, as well as shorter, while the terminal irregularities 
will usually have been effaced. The abbreviation of the calix may 
proceed to such an extent that one or two irregular indentations in 
the otherwise rounded contour of the true pelvis may alone remain. 
Accompanying these changes in the outline of the calix, a marked 
increase in the size of the true pelvis will usually occur. The pelvic 
outline is usually even and well rounded along its free border; this is 
typical of mechanical distention. Its size now makes it easily dis- 
tinguishable from a large, normal pelvis. This increase in size of the 
true pelvis may be out of proportion to the more moderate changes 
seen in the calices. With the increase in size of the true pelvis, the 
papillae which normally project between the major calices well into 
the pelvic lumen, become distinctly shorter and may become so 
flattened as practically to be effaced. 

Large hydronephrosis. — It will usually be difficult to demonstrate 
the entire contour of a greatly distended pelvis in the pyelogram because 
of the dilution of the injected medium by the retained fluid. The 
pelvis is now a large round sac, with rounded calices extending from 
it. The calices alone may be visible and appear as detached, irregular- 
ly rounded areas, particularly when partially filled. 

The ureter. — Dilatation of the ureter because of mechanical 
obstruction is characterized by an increase in the size of the lumen 
and by thinning of the ureteral wall. The degree of dilatation is 
greatest near the point of obstruction, and diminishes gradually as it 



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250 



W. F. BRAASCH 



nears the pelvis. This is in marked distinction to the inflammatory 
dilatation, which is often greatest at the ureteropelvic juncture and 
smaller in its lower portion. The degree of dilatation accompanying 




Fio. 115 (244137). — Cross section of ureter with chronic ureteritis. Note thickening 
of wall and dilatation of lumen. 

mechanical obstruction is usually greater than that resulting from 
infection. 




Fio. 116 (224202). — Microscopic section showing increase in size of lumen, leuko- 
cytic infiltration of submucosa and cicatricial changes in serosa. Comparative diminu- 
tion of muscle fibers. 

A stricture of the ureter may occur which obstructs the ureteral 
lumen only temporarily, 2 and it is possible that the ordinary method 



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DILATATION OF THE URETER AND RENAL PELVIS 251 

of cystoscopic examination may fail to disclose the presence of such 
a stricture, when examination is made during the interval of patency. 
A ureterogram may be of considerable value in such cases and may be 
the only method by which the condition can be demonstrated. 
Further, even though the existence of a stricture is ascertained by 
means of the ureteral catheter alone, its extent and the degree of 
dilatation above it can frequently be ascertained more accurately by 
means of the pyelo-ureterogram. When encountering an obstruction 
to the ureteral catheter, considerable difficulty may arise in differenti- 
ating an anatomic and a pathologic condition. The catheter may 
meet an obstruction at any level of the ureter, as the result of some 
anatomic condition, such as acute angulation in the course of the 
ureter, marked elasticity of the ureteral wall, or a loose mesenteric 
attachment. With most anatomic obstructions, an injected fluid 
will pass any obstruction offered to the ureteral catheter, and the 
absence of dilatation or any evidence of abnormality will demonstrate 
the anatomic nature of the obstruction. With a pathologic obstruc- 
tion, when the fluid gets by, a nodular dilatation about the obstruction 
or a diffuse dilatation of the ureter is visible. 



INFLAMMATORY DILATATION 

Any considerable degree of chronic infection involving the renal 
peivis and ureter will be followed by dilatation. This dilatation is 
not caused by a mechanical obstruction, but is the result of either a 
change in the tissues, and a consequent retraction in the walls of 
the pelvis and ureter, or of necrosis. The dilatation may vary from 
scarcely recognizable irregularity of the calices or dilatation of the 
ureter to complete destruction of the pelvis. 

The pelvis. — Dilatation of the renal pelvis as the result of inflam- 
matory changes :n its walls differs from mechanical dilatation largely 
in these characteristics: (1) predominance of dilatation in the calices 
or ureter rather than in the true pelvis, and (2) comparative ir- 
regularity of outline. It will be found that certain renal infections 
(evidently those predominant in the tissues adjacent to the renal 
pelvis) are usually accompanied by a considerable degree of inflam- 
matory dilatation largely in the calices, whereas, in the other renal 
infections (evidently those predominant in the renal parenchyma), 
the dilatation is confined to the ureter, with an actual decrease in the 



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252 W. F. BRAASCH 

size of the pelvis. The changes more commonly found in the outline 
of the renal pelvis as the result of an inflammatory process are: (1) 
dilatation confined largely to the calices; (2) dilatation involving the 
entire pelvis; (3) pyonephrosis; (4) contraction of the pelvis with the 
dilatation of the ureter; (5) alternating contraction and dilatation, 
and (6) atrophy. 

Dilatation predominant in the calices. — The earliest changes in the 
pelvic outline, as a result of infection, are commonly characterized 
by a slight broadening and irregular rounding or "clubbing" of the 
calices, with scarcely recognizable changes in the true pelvis. As 
the inflammatory process progresses, the dilatation in the calices may 
become well marked, while little or no dilatation may be apparent in 
the true pelvis. Marked dilatation of the upper ureter, particularly 




Fig. 117 (25012). — Cross section of tuberculous ureter. Specimen hardened; actual 
size of ureteral lumen not apparent. 

at the ureteropelvic juncture, is commonly seen with dilatation in 
the calices. 

Dilatation involving the entire pelvis. — With inflammation of long 
duration, dilatation of the true pelvis to a variable degree may also 
result. This occurs secondary to the dilatation in the calices, and 
is continuous with that in the ureter. 

Inflammatory contraction of the renal pelvis. — A decrease in the 
size of the pelvic outline frequently accompanies infection, which is 
largely confined to the renal parenchyma, involving the pelvis and 
ureter secondarily. The pelvis may appear markedly contracted, 
with narrow slits representing the calices. 

Destruction of pelvic outline^ or pyonephrosis. — With the extension 
of the inflammatory process and consequent destruction of the normal 
outline of the calices, the cortex may be invaded, and the resulting 
areas of necrosis may merge with the calices. The areas of cortical 
destruction which extend beyond the calices may be connected by 



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DILATATION OF THE URETER AND RENAL PELVIS 



253 



narrow isthmuses with the apexes, so as to give a very irregular outline 
to the pelvis. 

Alternating contraction and dilatation. — With a chronic inflam- 
matory process largely confined to the renal pelvis, its outline may 
become irregularly contracted as well as dilated. This may be due 
either to contraction as the result of inflammatory changes in the 
peripelvic tissues, or to encroachment on the lumen by inflammatory 
proliferation of the pelvic mucosa. 

Atrophic contraction of the pelvis. — An atrophic condition of one or 
of both kidneys is occasionally observed. Microscopic examination 



r B| 






P,- fc H 






\*f 




jf 




^>w 


L 


^^Hr" 


* 









Fig. 118 (25012). — Microscopic section of tuberculous ureter, showing round-cell 
infiltration of submucosa and cicatricial changes in serosa. 

of the renal tissue often demonstrates the existence of an etiologic 
inflammatory process. The resulting cicatricial changes may cause 
diminution in the size of the pelvis commensurate with the decrease 
in parenchyma. 

Inflammatory dilatation of the renal pelvis frequently accompanies 
renal stone, and may be of diagnostic value. The typical clubbing of 
the calices, with little or no dilatation of the pelvis or ureter, is fre- 
quently observed. That the stone could not cause mechanical obstruc- 
tion is evident from the fact that the stone may be securely lodged at 



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254 



W. F. BRAASCH 



the end of a calix. Such dilatation may be of definite value in inter- 
preting the identity of a small shadow in the renal area. 

The ureter. — As with inflammatory changes in the renal pelvis, an 
inflammatory process in the ureter is followed by tissue changes in its 
walls which cause more or less dilatation. The changes in the pelvic 
outline may be so slight as to remain unrecognized, whereas the dilata- 
tion in the ureter may be the only evidence of a previously existing in- 
flammatory process. The outline of the ureter, if well distended with 
mediums, will appear dilated as the result of infection. This dilatation 




Fig. 119(181497). — Mechanical dilatation. Microscopic 'section of a ureter dilated 
by a stricture. Note thinning of section of serosa and submucosa with comparative 
hypertrophy of musculature. 

is usually greatest near the ureteropelvic juncture, in contrast to the 
dilatation resulting from stricture of the lower ureter, which is usually 
greatest near the point of constriction. The ureter, particularly 
in its upper portion, is frequently tortuous, and occasionally appears 
markedly angulated. 

The portion of the ureter situated in the wall of the bladder will 
not become so dilated as the portion of the ureter above, unless the 
bladder itself is markedly inflamed. Dilatation of this portion of the 
ureter is the result of contiguous infection and is usually observed 
only with marked chronic infection of the bladder wall. On cysto- 



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DILATATION OF THE URETER AND RENAL PELVIS 



255 



scopic examination, no contraction of the dilated meatus may be 
visible, which would lead one to believe that with the alteration of 
tissue in the ureteral wall peristalsis is absent. Such dilatation may 
often be demonstrated by filling the bladder with an opaque solution 
and placing the patient in the Trendelenburg position, thus permitting 
the fluid to enter the ureter by gravity. This method will usually be 
found impossible unless the ureter in the wall of the bladder is dilated, 
since the contraction of the meatus and ureteric peristalsis would 
otherwise prevent the fluid from entering the ureter. Regurgitation of 




Fio. 120 (260776). — Typical inflammatory dilatation. Note distention of calicee 

Pelvis small. 

Madder fluid into the ureter, ascribed to insufficiency of the ureteral 
valve, has been noted by Hagner, Kretschmer and others. Hagner 
surmised that this was the result of inflammatory changes in the 
bladder wall. 

Ureteral dictation is frequently observed with prostatic obstruc- 
tion, and is usually ascribed to the result of mechanical distention. 
While this may be true in most cases, considerable ureteral dilatation 
has been observed in which the retention never was greater than 



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256 W. F. BRAASCH 

approximately 50 c.e. This usually occurs in the presence of a variable 
degree of chronic pyelonephritis, which is evidently the etiologic 
factor. 

Combined inflammatory and mechanical dilatation. — It must, 
of course, be considered that both inflammatory and mechanical 
factors may be present with ureteral and pelvic dilatation. Either 
factor may be the primary cause of dilatation with secondary influence 
of the other. Thus, a primary inflammatory dilatation, such as 
occurs with chronic pyelonephritis, may be complicated by a stricture 




Fig. 121 (230063). — Inflammatory dilatation, with cortical infection characterised by 
a decrease in the size of the pelvis and calices, and by a dilatation of the ureter. 

formation, with the usually subjective symptoms of urinary retention- 
Likewise, a primary stricture of the ureter will sooner or later cause 
urinary infection, together with an inflammatory invasion of the 
ureteral wall. In fact, it may be difficult to determine which was 
the primary factor. 

Pathology of the inflamed pelvis and ureter. — The frequency with 
which dilatation of the ureter and pelvis is observed at necropsy, 
when no evidence of mechanical obstruction can be found, has been 
noted by various observers. 11 With chronic infection of the pelvis 



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DILATATION OF THE URETER AND RENAL PELVIS 257 

and the ureter, a change takes place in their tissues which is evidently 
the cause of dilatation. When the pelvis is opened, the calices are 
usually dilated to a variable degree, and the pelvic wall is thickened. 
When dilatation of the true pelvis is present, it is not so great as that 
usually seen with mechanical obstruction to the ureter, nor is there 
such thinning of the walls. On inspection, the increase in size of the 
ureter is found to vary from a slight degree to a diameter of 2 cm. 
Dilatation to a greater degree than this is usually the result of mechan- 




Fio.122 (117716). — Atonic dilatation of the ureters resulting from lesion of the central 

nervous system. 

ical obstruction. On palpation, the ureter is discovered to be thicker 
than normal and firmer. This is particularly so with renal tuberculosis. 
On cross section of the ureter, the walls are seen to be hypertrophied, 
and the lumen is increased in proportion. With some cases of infection, 
the changes found in the ureter may be greater than those visible in 
the pelvis. A microscopic examination of the walls of the pelvis and 
the ureter reveals the abnormalities: (1) proliferation and often 
cornification of the mucosa; (2) a variable degree of leukocytic infiltra- 
tion of the submucosa and musculature; (3) a variable degree of 

'19-17 



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258 W. P. BRAASCH 

connective tissue change in the submucosa and serosa, and (4) a relative 
thickening, often to a marked degree, of the serosa. In the main, 
the inflammatory changes differ from the mechanical in (1) the greater 
degree of leukocytic infiltration; (2) in more marked connective tissue 
changes in the submucosa and serosa, and (3) in increase in thickness 
of the serosa. 

Data with renal tuberculosis. — Of particular interest is the dilata- 
tion which may occur with renal tuberculosis. The cystoscopic 
picture of a gaping, dilated meatus, with marked inflammation around 
it, while the other meatus is quite normal in its aspect, is familiar to 
us all in the classical picture seen with unilateral renal tuberculosis. 
The bladder in this condition is usually contracted, and the possibility 
of any mechanical obstruction in the urethra can usually be excluded, 
particularly when the condition occurs in the female. If a nephro- 
ureterectomy is made, the ureter is usually found with one or more 
strictures above the bladder wall. Occasionally, however, it may 
be found to be dilated throughout its entire extent, with absolutely 
no semblance of a constriction in any portion. The pelvis is often 
found to be slightly dilated; the calices to a variable degree, some 
very markedly, and some extending into the necrotic cortical areas. 
It would appear that any possibility of mechanical obstruction could 
be absolutely excluded, and yet there is a dilatation which remains 
to be accounted for. On microscopic examination, the walls of the 
ureter may fail to disclose any particular point of cicatricial narrowing, 
but will have the typical tissue changes seen with inflammatory 
reaction. 

ATONIC DILATATION 

Dilatation of the ureteral meatus, associated with paralysis of 
the bladder resulting from disease in the nervous system, was de- 
cribed by Koll. Such a dilatation occurs with only a small proportion 
of so-called "cord bladders." The dilatation of the ureter is not 
confined to the lower end, however, but may extend to the renal pelvis. 
Such a dilatation may in some instances be due to backing of the 
urine from the over-distended bladder; atonic ureteral dilatation may 
be found, however, when no residual urine is present. It is more 
probable that the same disturbance of innervation of the bladder 
also affects the ureter, particularly in its lower portion. With the 
relaxation of the bladder musculature, as frequently occurs with 



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DILATATION OF THE URETER AND RENAL PELVIS 259 

spinal cord disease, the ureter may relax to a proportional extent. 
That such a dilatation may involve the entire ureter can occasion- 
ally be demonstrated by a cysto-ureterogram. 

Another form of dilatation involving the ureter and pelvis has been 
described by Fedorow, Israel, Bachrach, Buerger, Kretschmer and 
others, a form in which no definite etiologic factor is evident. Neither 
mechanical obstruction, evidence of infection, nor disease of the central 
nervous system may be present. The ureteral meatus is gaping, the 
entire ureter dilated to a marked extent, and a variable degree of hydro- 




Fig. 123 (8886). — Typical mechanical dilatation. Note the large size of the true 
pelvis in proportion to the size of the calices. 

nephrosis may exist. This condition is usually bilateral, and has been 
variously ascribed to atony (Fedorow), spasmodic contracture of the 
bladder (Israel), inflammatory dilatation (Karaffa-Korbutt), and con- 
genital insufficiency of the ureteral sphincter (Bachrach). While 
the various authors differ widely with regard to the etiologic factor, 
they are all agreed in stating that no stricture can be demonstrated. 
We have observed 5 such cases at the Mayo Clinic, and the condi- 
tion was bilateral in all. One of the patients died following a cysto- 
ureteropyelogram, the medium used being collargol. On postmortem, 



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260 W. F. BRAASCH 

both ureters were found to be dilated throughout, and the kidneys 
were hydronephrotic. No evidence of mechanical obstruction was 
evident in any portion of the urinary tract, nor was there any clinical 
evidence of disease involving the central nervous system. 

Congenital stricture is such a rarity as to be an almost negligible 
factor. It is probable, furthermore, that many cases of dilatation 
reported as due to congenital stricture are really the result of an 
acquired mechanical obstruction. 

CLINICAL DATA 

When viewed from a clinical standpoint, the subjective data 
accompanying mechanical and inflammatory dilatation are quite 
distinct. It is difficult to conceive that there may be, without the 
presence of pain, an intermittent mechanical obstruction, with con- 
sequent overdistention of the pelvis and ureter by the retained urine. 
In the majority of cases the degree of pain is usually great, although 
it may be conceivable that with partial obstruction it might be of a 
moderate character. However, if the obstruction is sufficient to cause 
any marked degree of dilatation, the pain will be severe. With the 
dilatation such as is so frequently seen with chronic pyelonephritis, 
however, there is usually little or no pain referred to the kidney. We 
have repeatedly demonstrated marked dilatation, particularly of the 
ureter, which we regard as due to inflammatory causes, when the 
patient has complained of no pain whatever. In reviewing 240 cases 
of pyelonephritis, Thomas found that pain was present in less than 20 
per cent. If a history of definite pain is given, we have been led to 
believe that there must be some complicating mechanical obstruction. 

CONCLUSIONS 

1. Dilatation of the ureter and renal pelvis may occur without 
mechanical obstruction. 

2. The differences between mechanical and inflammatory dilata- 
tion, in their anatomy and pathology and in clinical data, are quite 
definite. 

3. The clinical demonstration of inflammatory dilatation may be of 
diagnostic value. 



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DILATATION OF THE URETER AND RENAL PELVIS 261 



BIBLIOGRAPHY 

1. Bachrach, R.: Ueber atonische Dilatation des Nierenbeckens und Harnleiters. 
Beitr. «. klin. Chir., 1914, lxxxviii, 279-286. 

2. Braasch, W. F.: Pyelography. Philadelphia, Saunders, 1915, 323 pp. 

3. Buerger, L.: Congenital hydro-ureter and hydronephrosis. Internat. Clin., 

1914, 24.s., iv, 243-249. 

4. Crabtree, E. G.: Pathology of tuberculosis of kidney and ureter. In: Cabot, 
H. H., ed., Modern Urology. Philadelphia, Lea and Febiger, 1918, ii, 509. 

5. Fedorow: Quoted by Karaffa-Korbutt. 

6. Hagner, F. R.: Regurgitation of fluid from the bladder to the kidney, during 
ureteral catheterization. Surg., Gynec. and Obst., 1912, xv, 510-511. 

7. Israel: Quoted by Karaffa-Korbutt. 

8. Karaffa-Korbutt, K. W. v. : Zur Frage fiber die Entstehung und die atiologisehe 
Bedeutung der Ureterenatonie. Folia urol., 1908, ii, 167-185. 

9. Koll, I. S.: A study of twenty-five tabetic bladders. Surg., Gynec. and Or St., 

1915, xx, 176-177. 

10. Kretschmer, H. L. and Greer, J. R.: Insufficiency at the ureterovesical junc- 
tion. Surg., Gynec. and Obst., 1915, xxi, 228-231. 

11. Robinson, B.: Potential obstruction of the tractus urinarius; occasional ncn- 
demonstrable causes of uro-ureter. Internat. Jour. Surg., 1909, xxii, 367. 

12. Thomas, G. J.: Clinical review of 240 cases of non-surgical infection of the kid* 
neys and ureters. Urol, and Cutan. Rev., 1916, xx, 127-180. 



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CONDITIONS CONTRA-INDICATING OPERATION 
WITH STONE IN THE KIDNEY AND URETER* 

W. F. BRAASCH 



Methods of diagnosis and localization of renal stones have been 
developed to such a degree of accuracy in recent years that the per- 
centage of error has been reduced to a minimum. When the diagnosis 
is established it is frequently of equal importance to determine the 
advisability of operation. Several circumstances should be con- 
sidered before operation is recommended. Among the most important 
of these are: (1) duration of symptoms; (2) size; (3) situation; 
(4) number of stones; (5) certain types of bilateral lithiasis; (6) low 
renal function; and (7) complications in other organs. 

Duration of symptoms. — The duration of symptoms should be a 
considerable factor in determining the advisability of immediate 
operation. It is not generally realized that probably 75 per cent of 
renal stones pass spontaneously. The majority of these stones will 
probably pass within three or four months following the first symptom. 
It may be stated, therefore, that it is usually inadvisable to operate 
for a stone in either the kidney or ureter until at least three months, 
and possibly six months, have elapsed since the onset of the symptoms. 
Immediate operation for stone following the first or second attack of 
pain, without evidence of other complications, is strongly to be con- 
demned. Nature should be given full opportunity to remove the 
stone without intervention. There maybe exceptions to this rule, 
of course, such as excessive pain continued over several weeks or 
months; evidence of acute cortical or perinephritic infeclion; and evi- 
dence of urinary retention sufficient to endanger the kidney. More- 
over, when it is evident that the stone is too large to pass nothing 
is gained by further delay even though the onset of symptoms is very 
recent. 

* Presented before the Southern Minnesota Medical Association, Mankato, 
November, 1919. 

Reprinted from Minn. Med., 1920, iii, 887-891. 

262 



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CONDITIONS CONTRA-INDICATING OPERATION 268 

Size of stones. — When the roentgenogram shows the stone to be 
less than 2 cm. in diameter, operation should be delayed in the hope 
of subsequent passage. When the stone is situated in the kidney and 
is less than 2 cm. in diameter, it may be very difficult to find at opera- 
tion, and the search may cause considerable destruction of renal tissue. 
The difficulty of search is increased and consequent destruction of 
tissue is greater when multiple small stones are present, even though 
the diagnosis is evident. When the symptoms are indefinite and the 
identification of the shadow uncertain, immediate operation should 
not be considered. When the symptoms are not too severe, and there 
is but little evidence of renal infection, it is advisable to defer operation 
until the stone has increased in size. 

Situation. — Stones situated in the renal cortex or in the end of the 
calices as a rule cause less damage to the kidney substance, and pro- 
duce less acute symptoms than stones situated in the pelvis. As a 
rule the urgency for operation for a stone in this situation is, therefore, 
not so great. When a stone is situated in the lower ureter, every op- 
portunity should be given for spontaneous passage unless previously 
mentioned complications are present. Repeated x-rays, taken at 
intervals, which show a change in position of the stone are indicative 
of its early passage. When the stone is situated in the bladder portion 
the possibility of its passage, naturally, is increased. Rarely is an 
operation indicated when a small stone is situated so as partially to 
protrude from the meatus. 

Number of stones. — When the roentgenogram shows the existence 
of more than one stone in the kidney or ureter, even though they are of 
a size which may pass spontaneously, it is usually advisable to operate. 
Conditions permitting the formation of multiple stones are usually 
surgical, and the time elapsing before spontaneous passage of such 
stones may permit of considerable renal damage. If one stone is 
situated in the ureter and the other in the kidney pelvis, if the stone in 
the ureter is larger, and efforts to remove it without operation have 
been unavailing, operation on the ureteral stone is indicated. If the 
renal stone which remains is less than 2 cm. in diameter, operation 
should be delayed in order to give the opportunity for the stone to pass 
spontaneously. 

Bilateral nephrolithiasis. — In the course of routine examinations 
stones will be found in both kidneys in approximately every sixth 
person suffering with renal lithiasis. Although surgical treatment 



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264 W. F. BRAASCH 

is usually advisable, conditions may be such that any operation for 
bilateral nephrolithiasis is definitely contra-indicated. When there 
are no acute symptoms and when the stones in both kidneys are very 
large and multiple operation is usually inadvisable. Removal of 
such stones situated in both kidneys is usually accompanied by con- 
siderable destruction of the kidney tissue, and the chances are that the 
patient would live as long and as comfortably without operation. 
When the symptoms are acute and unilateral, however, operation is of 
course indicated. 

Renal function. — Clinical and laboratory evidence of a very low 
renal function should usually contra-indicate operation when the 
symptoms are not very acute or persistent. Operation may be 
justifiable with acute symptoms, however, even though the renal func- 
tion is far below the normal. It is surprising how well patients with a 
functional test of less than 20 per cent phenolsulphonephthalein will 
react following the removal of a renal stone. Furthermore, a renal 
functional test of from 20 to 30 per cent in the presence of lithiasis, 
particularly when bilateral, will frequently become approximately 
normal after the stones have been removed. When the phenolsul- 
phonephthalein return is only a trace, however, and the urea retention 
is high, operation should not be considered unless the symptoms are 
urgent. Renal stone occurring with chronic nephritis is observed 
occasionally. The removal of such a stone will usually not affect the 
course of the primary nephritis and, unless the surgical indications are 
urgent, operation is inadvisable. Stone occurring with bilateral 
pyelonephritis, however, should be removed even though the symptoms 
are not urgent. Removal of such stones will usually have a favorable 
effect in that it tends to diminish the infection and further the benefit 
derived from pelvic lavage. It is advisable to ascertain the function 
of the opposite kidney before operating for renal stone, since the nec- 
essity for nephrectomy may be found on exploration. When the 
opposite kidney is practically functionless or when it is absent a con- 
servative operation is necessary. Operation for stone in polycystic 
kidney has been done in the Mayo Clinic in 5 cases. Although 
operation on a polycystic kidney is usually inadvisable, acute symp- 
toms caused by the secondary formation of stone may necessitate 
surgical relief. Nephrectomy is indicated only when a complicating 
infection has rendered the affected kidney functionless. A careful 
estimate of the comparative renal function is indispensable in cases 



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CONDITIONS CONTRA-INDICATING OPERATION 265 

of polycystic kidney. When glycosuria is present, the same pre- 
cautions should be observed which are necessary in surgery in any 
other portion of the body, that is, the reduction of sugar by dietary 
and other means, and operation only when absolutely necessary. 

Coincident disease. — Lesions in other organs are frequently noted 
coincident with renal lithiasis and they may influence the advisa- 
bility of operation. The presence of a coincident lesion may bring 
up the question of which lesion should have precedence in treatment. 
When the several conditions are surgical the lesion which causes the 
most acute symptoms naturally necessitates operation first. In the 
long list of coincident diseases, lesions in the alimentary tract and 
renal lithiasis are the most common. Surgical, lesions in the gall- 
bladder, appendix, and duodenum coincident with renal lithiasis occur- 
red in more than 10 per cent of the patients operated on in the Mayo 
Clinic. The coincident lesion may be such that operation on the kid- 
ney should be postponed or even permanently contra-indicated. 
Certain forms of cardiac diseases when advanced may render such 
an operation inadvisable even though no evidence of decompensation 
may be present at the time. This is particularly true in the aged. 
It is not to be inferred, however, that cardiac lesions which are well 
compensated or of moderate degree will offer any contra-indication 
to renal operation. 

Hypertrophy of the prostate gland coincident with renal lithiasis 
is occasionally observed. In cases in which most of the symptoms are 
caused by the prostatic obstruction, prostatectomy is indicated after 
the usual course of preparation, provided that the other kidney is 
normal. When the renal symptoms are so acute as to require primary 
operation the degree of urinary retention is of considerable importance. 
When a large amount of residual urine is present a preliminary drainage 
and its usual reaction should precede the renal operation if possible. 

Pregnancy, particularly of less than six months, offers no contra- 
indication to operation. If the symptoms become acute and persis- 
tent it may be necessary to operate as an emergency measure even in 
the later months. As a rule, however, in the latter period of pregnancy 
it is advisable to defer any operation. Unilateral lithiasis should not 
cause any serious complication during the course of pregnancy or 
labor. With bilateral nephrolithiasis, however, renal insufficiency 
may interfere to such an extent that induced labor may be necessary. 

During the years 1917 and 1918, 79 cases were diagnosed renal 



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266 W. F. BRAASCH 

lithiasis at the clinic in which operation was not advised. In this 
group the various causes assigned were as follows: 

Cues 
Operation deferred because of indefinite diagnosis either from clin- 
ical or roentgenographic and cystoscopic data ; 43 

Lesions of the central nervous system 1 

Advanced pregnancy 2 

Bilateral nephrolithiasis with evidence of uremia S 

Hypertrophy of the prostate with renal insufficiency S 

Excessive adiposis with indefinite symptoms 1 

Advanced age 2 

Advanced malignancy in other tissues 2 

Advanced disease in the other kidney; renal insufficiency 1 

Advanced bilateral pyelonephritis 2 

Advanced cardiac disease 6 

Chronic nephritis 2 

Hypernephroma of the opposite kidney 1 

Bilateral nephrolithiasis with pregnancy 1 

Myocardial disease and goiter 1 

Active lues 2 

Advanced diabetes 1 

Bilateral pyonephrosis 1 

Single kidney with indefinite shadow 1 

Active bilateral pulmonary tuberculosis 1 

Polycystic kidney with renal insufficiency 1 

Advanced Hodgkin's disease 1 

From this it may be inferred that the diagnosis of renal stone may 
be of secondary importance in the clinical summary, and that the 
conditions which may contra-indicate lithotomy are many. 

Stone in the ureter. — In recent years numerous articles have appeared 
with reference to the removal of stones in the lower ureter by non-opera- 
tive methods. Some authors in their enthusiasm claim that it is no 
longer necessary to operate for ureteral stones since they cari all be 
removed by cystoscopic manipulation. In a previous article I re- 
viewed the methods employed to remove stones in the lower ureter 
and reported 64 cases in which the stone had been successfully removed. 
Since then we have been able to bring about the passage of stones in 
62 more patients, or in 126 in all. It has been our experience that 
approximately half of the stones in the lower ureter that will not 
pass spontaneously can be removed successfully by non-operative 
measures. This proportion will be greater in larger communities in 
which the more acute cases with histories of recent symptoms may be 
observed by the surgeon. In a large number of these early cases 



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CONDITIONS CONTRA-INDICATING OPERATION 267 

small stones would probably have passed spontaneously even though 
no cystoscopic manipulation had been made. When the stone has 
been lodged in the lower ureter during a period of more than from 
three to six months, and when it is more than 2 cm. in diameter, the 
possibility of its dislodgment by cystoscopic methods is greatly dimin- 
ished. In justice to the patient, however, an attempt should be made 
in every case to dislodge the stone before resorting to operation. It 
is frequently surprising that by simply dislodging a stone which has 
been causing symptoms over many months it will be passed by the 
patient with the next colic. Recent observers have given much 
importance to the value of drugs which cause the ureter temporarily 
to relax. It is very questionable, however, what bearing such tem- 
porary relaxation could have. Of greater importance is the fact that 
the stone has been removed from its anchorage by the ureteral catheter, 
dilating sound or instrument which has come in contact with it. Defi- 
nite contra-indication to further attempts to dislodge the stone, how- 
ever, may be: (1) a stone more than 2 cm. in diameter; (2) acute 
impaction with continuous obstruction; (S) acute renal infection; 
(4) intolerance on the part of the patient to the cystoscope; and (5) 
anatomic deformity. 

In conclusion I would emphasize the facts that the great majority 
of renal and ureteral stones will pass spontaneously, that a large 
proportion of stones in the lower ureter which do not pass after one 
or two attacks of colic can be dislodged by cystoscopic manipulation, 
and that immediate operation for small stones, which have caused 
recent symptoms, is seldom justifiable. 

BIBLIOGRAPHY 

1. Brsasch, W. F. and Moore, A. B.: Stone in the ureter. Jour. Am. Med. Assn., 
1M5. Ixv, 1*34-1237. 



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STONE IN THE KIDNEY* 

C. H. MAYO 



In medical progress the means of relief by therapeutic measures 
or surgery have far outstripped our knowledge of the cause of disease. 
The etiology had been proved in a sufficient number of instances, 
however, and reasoning by analogy in other diseases had led to measures 
of prevention and control of many of the common ailments before the 
identity of the bacterial agents was known. Medicine is in its most 
interesting phase, namely a consideration of the etiology which carries 
investigation into the field of biochemistry, the newer physiology, and 
like sciences. The philosophic view of bacteria is to consider them 
necessary to life as the minute chemists of the air, the water, and the 
soil. But few of their countless numbers are the cause of disease by 
being misplaced in their activity, and only a small number, possibly, 
are natural disease-creating organisms. 

THE FORMATION OF STONE IN THE KIDNEY 

Crystaloids probably form in the structure of the kidney, the cortex 
and the surface, without local infection, the result of a rare unbalanced 
contest constantly ensuing between crystaloids and colloids. Stones 
in the kidney, ureter, or bladder undoubtedly originate in the kidney 
except those which develop from foreign bodies in the bladder. The 
cause of stone in the kidney has long been a subject of discussion; the 
old and simple theory that they grew, like Topsy, is no longer satis- 
factory, and some of the other theories that have been advanced, al- 
though most interesting, are not generally accepted. An acceptable 
scheme of stone formation must be applicable to the several regions 
in which stones are found and it must not differ materially for any 
locality. Morris considers two types of stone, the first due to urinary 
salts or ingredients precipitated from the urine in the kidney, independ- 

* Presented before the Southern Surgical Association, New Orleans, December, 1919. 
Reprinted from Ann. Surg., 1920, lxxi, 123-127. 

268 



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8TONE IN THE KIDNEY 269 

ent of any change in that structure or of infection, and the second, 
to precipitation due to chemical changes caused by microorganisms. 
An analysis of stones in the Hunterian Museum has shown a urate 
nucleus in stones forced in infancy, a uric acid nucleus in stones removed 
from young adults, and an oxalate nucleus in stones removed from 
patients in middle life. 

Two-thirds of the kidney stones giving trouble are found in patients 
in the third and fourth decades, although the stones appear in every 
decade of life. Certain observers hold to the theory that a slowing 
of the delivery of urine in limited areas leads to increased concentra- 
tion and deposit of salts. In denying the infection theory they call 
attention to the fact that renal stones are more often found in men 
than in women, although the female genito-urinary tract is more likely 
to be infected. According to their theory, therefore, an increased 
number of stones should form following mechanical interferences in 
areas of the pelvis with the passing of urine, such as partial ureteral 
obstruction and extraneous pressure from glands, tumors, or preg- 
nancy for instance; but this does not appear to be the case. Hunner's 
theory is not generally accepted, that the over-saturated urine forms 
stones which originate in the ureter above a stricture of large caliber 
and may float back into the pelvis of the kidney. It is barely possible 
that the infection causing stricture may be furnishing mucoid, the 
cause of stone formation in such a condition. If these hypotheses 
were true, the number of cases of stone from such causes would be 
greatly added to by the partial compression of anomalous vessels 
acting on the ureteropelvic juncture in unusual mobility of the kidney, 
first shown by W. J. Mayo and later by Rupert to be a very common 
condition. 

Stones are frequently found in both kidneys. Braasch found bi- 
lateral lithiasis in 12.3 per cent of 450 cases of nephrolithiasis. Many 
patients with stone in the kidney have no pain, and 65 per cent with 
stones in both kidneys have pain on one side only. Cabot by means 
of repeated tests showed that there are no abnormal urinary findings 
in 14 per cent of the cases of stones in the kidney and ureter. The 
kidney is an organ of filtration and is constantly eliminating bacteria 
from the circulation. These are many in variety and, without some 
contributing circumstances, apparently do not injure the urinary 
tract in their passage through the kidney, ureter, and bladder any 
more than bacteria on the skin or those passing through the alimentary 



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270 C. H. MAYO 

tract or normally living there cause trouble in those regions. Some 
types of bacteria produce infarctions in minute clumps of capillaries 
and following surgical conditions gross kidney infarctions and infec- 
tion which cause death are occasionally seen. The minute hema- 
togenous infections at the boundary of the terminal circulation in the 
cortex of the kidney at its juncture with the tubules are seldom exten- 
sive enough to create more of a change in the patient's general health 
than an acne pustule on the face. The eliminating surface of the kid- 
neys probably equals that of the skin covering the body, but the latter 
has the power of cell growth given to epithelium for restoration as an 
additional protection. The infection theory seems the only tenable 
one, but I contend that the development of stone requires the presence 
of two factors of infection, that is, two types of bacteria, one producing 
the hematogenous infection, and one only coming from a local focus; 
the second may but temporarily inhabit the blood in the process of 
elimination. Bacteria of the stone-forming type must come in con- 
tact at the proper time, a brief period only, in which the mucoid exudate 
is present as a result of the first infection. 

It seems hardly possible that the lime content of food or drink, 
which it must be admitted varies greatly, has very much to do with 
the origin of stone, although it might influence the rapidity of the 
growth of the stone. The origin of stone in the kidney is no more 
mysterious than that of stone on the teeth of infected mouths, which 
requires a chisel and hammer for removal; saliva resembles the mucoid 
giving foot-hold through diseased gums for types of bacteria of the 
proper strain and stone formation ensues; this is true also in the de- 
velopment of gallstones which form only in an infected gallbladder. 
A step further is the development of the shells of the fresh and salt 
water mollusks. We think of them as having been built by the 
mollusk; in reality they are built by bacteria feeding on the pabulum 
of his exuded mucoid material, according to which the natural type of 
shell is constructed from the solutions held in the water of the sea or 
river, the bacteria doing the work for bed and board, the mollusk 
furnishing the muscle hinge. If these bacteria become misplaced 
within his body a pearl or slug develops as the result of his disease. 
Such life can be reproduced only in limited areas of sea or river beds 
where the bacteria grow in great numbers, producing clam and oyster 
beds. The work done by such bacteria is no more important than 
that of the insects which fertilize the fruit flowers. 



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STONE IN THE KIDNEY 



271 



Stones form in the cortex, in the calices, and in the pelvis of the 
kidney. The kidney is constantly eliminating living bacteria, so that 
it is always exposed to infection, and usually shows no results from it 
except gross lesions of rare occurrence. Stone formation may proceed 





' 










* * ■ 




J J 




i^ ; fl 




_^j 


K 




^B 


m 






« 










^B 


fo>*' 







Fio. 124. — Infected hydronephrosis with multiple nephrolithiasis. 

with exceeding slowness, and without pain or other symptoms until 
marked destruction of the kidney occurs, mixed infection develops, 
or until the stone assumes great size or becomes loosened and moves 
into the ureter (Fig. 1 24) . Minute infarctions occur as shown at necropsy 
following death from an acute attack, and the results of similar lesions 
in the past are shown by scars or gross kidney change. 



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272 



C. H. MAYO 



Stone formation is evidently the result of the combination of two types 
of bacteria; the first creates an infarction with minute necrosis causing 
mucoid exudate forms; the second factor is the elimination at the same 
time of the stone-forming bacteria that they may come in contact 
with the mucoid material. If the stone originates in the cortex 
of the kidney its growth will be slow, but if it originates in the calices 




Fio. 125. — Hydronephrosis with oval stone. 

or pelvis growth may be much more rapid because of the ease with 
which its chemical material is secured. 

Stones in the kidney vary in chemical composition but are homogen- 
eous; they are round, irregular, multiple or branched, coral-like (Figs. 
125 and 126). Those forming or increasing in the urinary bladder 
often form rings of varying widths, as shown by cross section. During 
growth stones are covered with mucus and the changes in structure 



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STONE IN THE KIDNEY 



273 



probably have to do with the mucoid material on the stone or changes 
in the metabolic process so that the structure varies with changes in 
the number of the workmen or the material supplied them. Bacterial 
types differ in their handling of material as much as masons differ in 
the use of brick, stone, and cement. It is of interest to note that young 
oysters transplanted from the shores of England to the Mediterranean 



U*ces coat 



> broken, j-fonx la,rde sion,* 




Fig. 126. — Coral-shaped stone with hydronephrosis of the kidney. 

oyster beds will have the ray shells formed by the new bacterial archi- 
tects, 10 a fact of importance in considering branched coral-like stones in 
the kidney. Medical treatment in principle is based on a change in 
the chemical conditions of urine or local environment created by food 
changes, by dilutions, or by elimination of various chemical bacterial 
detritus. In the review of a limited number of cases in which operation 



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274 C. H. MAYO 

was done during the formative period of surgery of the kidney Cabot 
found that stone in the kidney reformed in 49 per cent, and stone in 
the ureter in 29 per cent. Braasch in a consideration of 450 cases of 
stone in the kidney in which operation was performed showed that the 
recurrence was slightly under 10 per cent. We believe that this better 
result is due to more careful examinations made within the last few 
years, to the greater facilities for all kinds of tests, including roentgen- 
ography, especially after operation, in order to discover whether or not 
a stone has been overlooked; the roentgenogram occasionally shows 
surprising results in cases of small multiple stones. More careful 
search must be made for extra stones, since superimposed stones may 
give but one shadow. 

The mortality is low in operations for the removal of stone in the 
kidney. The reports from the clinic (Table 1) show that the mortality 
percentage has risen during the past three years over that of the years 
from Jan. 1, 1898 to Dec. 31, 1915; this is no doubt due to the greater 
risks which have been taken, but which have resulted in the saving 
of an increased number of lives. 

Table 1. — Results of the Removal of Stones from the Kidney 

Number of Number of Deaths 

patients operations 

Jan. 1, 1898 to Dec. 31, 1915 450 484 S (0.62 per cent) 

Jan. 1, 1916 to Dec. 1, 1919 487 499 8 (1.87 per cent) 

937 983 11 (1.12 per cent) 

In closing I wish to call attention to a plan devised by Dr. Braasch 
and Dr. Carman of the clinic to prevent overlooking stones in the kidney 
at operation and to facilitate search for small stones giving symptoms 
that are difficult to locate in the pelvis, the calyx, or the cortex of the 
kidney. In the course of the operation the kidney is elevated into the 
incision, above the level of the skin if possible, where it is held by an 
encircling pack of gauze; a portable x-ray apparatus of the army type 
is moved to the side of the operating table and under the darkened glass 
and hood the roentgenologist is at once enabled to locate the stone 
and to point out the location with an aseptic glass rod, or, what is just 
as important, and occasionally occurs, he proves that the shadow seen 
in the roentgenogram was not due to stone in the kidney, and thus 
prevents serious injury to the organ by a fruitless search. The roent- 
genologist wears darkened glasses for fifteen minutes before attempting 



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STONE IN THE KIDNEY 275 

such an inspection. The operating room is darkened and the operator 
works under electric light which can be turned off and on. 

BIBLIOGRAPHY 

1. Braasch, W. F.: Lithiasis with bilateral renal involvement. Boston Med. and 
Surg. Jour., 1918, clxxviii, 292-298. 

2. Braasch, W. F. and Carman, R. D.: Renal fluoroscopy at the operating table. 
Jour. Am. Med. Assn., 1919, lxxii, 1751-1752. 

S. Cabot, H.: Errors in diagnosis of renal and ureteral calculus. Tr. Am. Assn. 
Genito-urinary Surgeons, 1915, x, 258-264. 

4. Cabot, H. and Crabtree, £. G. : Frequency of recurrence of stone in the kidney 
ifter operation. Surg., Gynec. and Obst., 1915, xxi, 228-225. 

5. Hunner, G. L.: The etiology of ureteral calculus. Surg., Gynec. and Obst., 
1918, xxvii, 252-270. 

6. Mayo, W. J., Braasch, W. F. and MacCarty, W. C: Relation of anomalous 
renal blood vessels to hydronephrosis. Jour. Am. Med. Assn., 1909, Hi, 1383-1388. 

7. Morris, H.: Surgical diseases of the kidney and ureter. New York, Cassell, 
MM, ii, 70; 74. 

8. Rupert, R. R.: Irregular kidney vessels found in fifty cadavers. Surg., Gynec. 
and Obst, 1913, xvii, 580-585. 

9. Rupert, R. R. : Further study of irregular kidney vessels as found in one hundred 
eighteen cadavers. Surg., Gynec. and Obst., 1915, xxi, 471-480. 

10. Turnbull, A.: The life of matter. London, Williams and Norgate, 1919, p. 82. 



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THE RESULTS OF OPERATIONS FOR THE REMOVAL 
OF STONES FROM THE URETER* 

E. S. JUDD 



Within the past few years many ingenious non-surgical methods 
for the removal of stones from the ureter have been devised and 
described, thus greatly reducing the need for operation in these cases. 
It is first to be desired in cases of stone. in the ureter that the stone shall 
pass voluntarily into the bladder. In some instances this will occur 
during the first attack of pain although usually several attacks are 
required to force the calculus through. Without special investigation 
of this subject it may not be realized how many persons pass stones 
spontaneously. I have known of 12 per cent of a group of about 400 
persons to respond in the affirmative when they were questioned 
with regard to the passing of stones. 

The published data and our own experience seem to show that most 
of these calculi originate in the calices and in the kidney pelvis. In 
some of the cases in which there is an associated stricture of the ureter 
the stone may originate at the point of the stricture, as suggested by 
Rovsing and Hunner; in most of our cases, however, in which a definite 
firm stricture was found there was no evidence of a calculus. 

The symptoms produced by ureteral calculi are usually very definite 

and suggest the condition even though in a number of cases the stone 

may lie in the ureter for a long time without any apparent changes or 

symptoms. In several such cases we have not seen changes of any 

consequence in the ureter or the kidney, nor evidence of interference 

with the passage of urine. In by far the larger number of cases the 

characteristic symptoms are manifest, but the syndrome must not be 

depended on for the diagnosis since it may be misleading; a variety 

of other conditions may produce nearly the same syndrome and, 

furthermore, an accurate and dependable diagnosis can be made in 

nearly every case by the use of the x-ray combined with the opaque 

* Presented before the Southern Surgical Association, New Orleans, December, 1919. 
Reprinted from Ann. Surg., 1920, lxxi, 128-138. 

276 



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REMOVAL OF STONES FROM THE URETER 277 

catheter and ureterogram, and in some cases the wax-tip catheter. 
In doubtful cases in which it is necessary to exclude the possibility 
of the x-ray shadow which is being produced by an extra-ureteral 
structure, Dr. Braasch employs ureterograms, and by this method has 
reduced the possibility of error to an inconsiderable degree. 

When the diagnosis has been made and the exact location of the 
stone is determined there are several points to be considered regarding 
the plan to follow. We must first remember that in many cases the 
stones will pass of their own accord so that if the patient is having 
frequent and severe attacks of pain it will probably be best to keep 
him under observation for a reasonable length of time in the hope 
that the stone may pass unassisted. During this waiting period, how- 
ever, the possibility of too severe pressure in the ureter and kidney and 
of a permanent hydronephrosis or pyelonephrosis should constantly 
be kept in mind in order that this waiting time shall not be too pro- 
longed. In cases in which the stone apparently is not causing symp- 
toms, even when it is discovered in the course of a routine examination, 
its removal is advisable unless there is some contra-indication. In all 
the cases in which the stone does not pass readily of its own accord it is 
best to consider the non-operative methods of treatment. 

Patients with stone in the ureter who come to the clinic for treat- 
ment are seen and . examined in the Section of Urology. After the 
diagnosis has been made the non-operative methods are employed. 
Braasch, 2 who has removed about 126 calculi in this manner, dislodges 
the impacted calculus by a ureteral catheter or a small sound. His 
results have been very satisfactory, and he believes that all patients 
should have the benefit of an attempt to remove the stones without 
operation. Braasch 's definite contra-indications to further attempts 
to dislodge stones are: (1) a stone 2 cm. or more in diameter, (2) acute 
ossification with continuous obstruction, (3) acute renal infection, 
(4) the patient's intolerance to cystoscopic manipulation, and (5) 
anatomic deformity. If the renal infection is severe intra-ureteral 
methods should not be attempted, and the operation should be under- 
taken with the idea that it may be necessary to remove the kidney. 
The results of non-operative methods to give the best results will 
depend largely on the manner in which they are used. Braasch has 
obtained excellent results by dislodging stones with ureteral catheters 
and he has also had some good results with papaverin. In nearly all 
the cases in which the stone presents at the ureteral orifice he has 



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378 E. S. JUDD 

succeeded in removing it by means of the Bransford Lewis and other 
types of instruments. It is difficult to decide just how many times 
these non-operative measures should be repeated; the success of the 
attempt and the pain and discomfort to the patient may well be decid- 
ing factors. In some cases, undoubtedly, such treatments have been 
carried too far, producing infection in a normal kidney, and consider- 
able trauma to the ureter and bladder. It should be borne in mind 
that while this non-operative treatment was being perfected many 
improvements were made in the surgical treatment, and the results 
of operative procedures are now very satisfactory. 

A stone lodged in the ureter may result in pathologic changes in 
several different tissues. In many cases the ureter is dilated above 
the stone and in some instances this dilatation is marked, so that the 
ureter seems almost as large as the small intestine. In such cases the 
wall of the ureter is thick, with definite signs of inflammation. At 
times the stone completely blocks the ureter and there is an accom- 
panying hydronephrosis. Unless the kidney is extensively infected 
it need not necessarily be removed, since after the stone is removed 
sufficient renal function may remain to warrant saving the kidney. 
The same condition may result whether the stone is large or small. 
Contrary to this is the case in which the ureter, on exposure, appears 
normal in size and appearance, a condition noted in many of our cases. 
The stone seems almost to fill the lumen of the ureter and yet there is 
no dilatation and no evidence to show that the ureter has previously 
been dilated. The improbability that these stones descend through 
the apparently normal ureters seems to be evidence of the fact that 
some of these calculi may form in the ureter itself, possibly at the site 
of a stricture. This type of stone is small and is often located with 
difficulty in a seemingly normal ureter. It is undoubtedly true that 
stricture of the ureter occurs in association with stone, and it is quite 
probable that in some of our cases in which there was not immediate 
complete relief of symptoms after the stone was removed that a 
stricture caused the trouble. I have been impressed with the infre- 
quency of any gross evidence of a stricture. Even in cases in which 
difficulty was experienced in removing an inaccessible stone and in 
those in which the stone had perforated the ureter and produced much 
peri-ureteral infection we have not seen a stricture of any consequence. 
In some of our cases there was delay in the closure of the urinary sinus, 
but in all the sinus was completely closed within a few weeks, and no 



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REMOVAL OF STONES FROM THE URETER 279 

permanent fistulas occurred. There must have been stricture in some 
of our cases, but ,1 believe that in most instances the condition is spon- 
taneously relieved. 

The same conditions follow the removal of stone by the non-opera- 
tive and the operative methods. In several cases we have found the 
ureteral calculus lying in an abscess cavity outside the ureter, and in 
all of these the condition was relieved by the removal of the stone from 
the abscess pocket and drainage of the abscess without any endeavor 
to manipulate the ureter. If a pyelonephritis has resulted from the stone 
and there is no evidence of more or less general infection it is advisable, 
if there is a good functionating kidney on the opposite side, to remove 
the stone and establish drainage. In many of these cases the damage to 
the kidney is already beyond recovery, the immediate results will not 
be satisfactory, and the kidney will have to be removed later. In the 
extreme case, if the stone is in the lower third of the ureter so that a 
very large incision, or in some instances two incisions, would be 
required to remove the kidney and the ureteral stone, it is best to re- 
move the kidney and leave the ureter and stone, removing the stone 
later if necessary. In two of our cases we were obliged to remove the 
calculus from the ureter at a later date because of pain. Before opera- 
tion it may be impossible to determine the amount of function in the 
affected side as it is sometimes impossible to collect the urine because 
of the presence of the stone. In these cases I believe the best plan 
is to remove the stone and preserve the kidney if we are not aware of 
infection in the kidney at the time. Conservative methods are 
justified in any case of chronic infection of the kidney, but radical 
methods must be employed in acute severe infection, and nephrectomy 
should be done before severe uremia and toxemia threaten. 

In two of our cases complete anuria was produced by stone in the 
ureter. In Case 1 (A195194), the patient had been operated on by 
Dr. W. J. Mayo five weeks before for hypernephroma of the left 
kidney. The patient made an uneventful recovery from the nephrec- 
tomy, was discharged from the hospital, and was about to leave for 
home when he noticed that his urine had diminished greatly. He 
told of having passed stones, probably from the right side, some time 
before and of having colic, which suggested a stone on the right side. 
Finally the urine stopped completely and treatment was instituted for 
suppression, but aside from the fact that there was a little evidence of 
edema the patient did not appear to be sick. Dr. Crenshaw cath- 



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280 E. S. JUDD 

eterized the right ureter and met an obstruction about 5 inches from 
the bladder which the x-ray showed to be a stone. The patient had 
passed no urine for six days when I operated, removing the stone from 
his right ureter. The ureter was greatly dilated and filled with turbid 
urine. The kidney started to functionate apparently as soon as the 
pressure was relieved, a large amount of urine was secreted, and the 
patient made a complete recovery. 

In Case 2 (A205789) the man gave a history of having been oper- 
ated on several months before for stone in the left ureter. He came 
to the clinic because of a persistent urinary sinus through the scar 
on the left side. Dr. Braasch's examination revealed a stone in the 
right ureter about 6 inches from the bladder, and a ureteral catheter 
was passed to the scar of the operation on the left ureter. The patient 
was passing about equal amounts of urine from the bladder and the 
sinus in the left flank. Shortly after the examination the urine stopped 
completely. We tried again to probe the urinary sinus on the left 
side but were not successful. For six days there was no urine passing 
from the sinus or the bladder and yet the patient apparently was hav- 
ing no trouble because of it. I then removed a stone from the right 
ureter which was greatly dilated and filled with turbid urine as in 
Case 1. Because of the evident infection no effort was made to close 
the opening in the ureter and the urine drained for several days, after 
which the wound healed completely. At this time the sinus on the 
left side, which we had not been able to open with a probe, opened 
spontaneously and drained urine. A month after removing the stone 
from the right side, I operated through the scar on the left side, and 
closed the left ureter which was greatly scarred and thickened. Exam- 
ination of the ureter revealed no cause for the persistent sinus and 
trouble except extension of scar tissue and stricturing. I excised much 
of the scar tissue and reconstructed the ureter over a small tube, which 
was pushed down the ureter so that it projected into the bladder. 
The tube was removed some days later by means of the cystoscope. 
The sinus did not reform and the ureter. was patent at the time the 
patient was discharged. 

The most striking feature in both these cases is that, in spite of 
the fact that no urine escaped for six days, the patients did not appear 
to be sick. 

In our few cases of bilateral ureteral calculi, it has seemed best 
to remove the stones by operation rather than by non-operative 



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REMOVAL OF STONES FROM THE URETER 281 

methods. We usually operate on one side at a time, although in some 
instances we have removed stones from both ureters at one operation. 
The side showing evidence of acute trouble is operated on first; if 
there is no apparent difference we prefer to remove the stone from 
the ureter on the side having the best function. 

The cases in which operation has been done between the years 1901 
and 1918 are tabulated in Tables 1 to 14. During this same time, 
Dr. Braasch has removed ureteral stones in 126 cases by non- 
operative methods. During the same period we operated on 400 
patients. In our earlier cases no attempt was made to remove the 
stone by non-operative methods. We find it is difficult to estimate 
just what percentage of ureteral calculi may be removed by non-opera- 
tive methods, but probably the percentage is often given too high. 
Roughly estimated, I should say that at the present time about one- 
half the patients require operation in order to rid them of the stone; 
in other words, they will be better off if the stone is removed by 
operation. 

Forty-eight (12 per cent) of the 400 patients operated on had 
passed stones or gravel before operation; in 9 cases multiple stones, 
averaging 6, had been passed, and yet in all these cases impaction of a 
stone in the ureter necessitated operation. 

The diagnosis of ureteral stone by x-ray and cystoscopy has been 
developed almost altogether since 1901, so that a much higher per- 
centage of accuracy in diagnosis will be found in the later cases than 
in the cases of earlier years. 

Our study shows that the results of operations for the removal of 
stone in the ureter have been almost universally satisfactory. Of this 
series of 400, two of the patients operated on have died and only one 
of these deaths could be attributed to the operation. In the first case 
an infected appendix was removed; the patient had a left hydro- 
nephrosis and a right-sided nephritis; he died of peritonitis. In the 
second case death resulted at about the end of two weeks from infec- 
tion and extravasation of urine. 

Convalescence following the operation is usually short and not 
attended by any difficulties. In some instances the urine drains 
freely for several days, and in others, even though the opening in the 
ureter has not been closed, there will be very little if any drainage. 
In the non-infected cases in which it is feasible to close the opening in 
the ureter, the wound heals primarily. 



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282 



E. S. JUDD 



During the past few months, Dr. Scholl has made a careful review 
of the histories of these cases, and has sent out "follow-up" letters to 
all the 400 patients; answers have been received from nearly 300. 
In approximately 90 per cent of these complete relief of former symp- 
toms had ultimately resulted. A number of the patients mentioned 
the fact that they had pain in the same side and of the same character 
persisting for several weeks after the operation, but in most instances 
by the end of six months the pain had entirely disappeared. Twenty- 
one patients had pain severe enough at some time or other to require 



kncision. 




Fig. 127. — The midline incision is used when it is necessary to explore both ureters. 

morphia. About 15 per cent of the patients complained of frequency, 
and some of them of hematuria lasting for several weeks after the 
operation, thus showing that the infection which existed at the time 
of operation had a tendency to clear up later. Twenty-six of the 400 
patients have passed stones since the operation. Of course it is im- 
possible to say whether these stones came from the kidney, the ureter 
on the side operated on, or the opposite side. 

The technic of the operation for the removal of stone from the 
ureter differs according to the location of the stone. If the stone is 



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REMOVAL OF STONES FROM THE URETER 



283 



situated at the uretero-pelvic juncture, or at any place in the upper 
third of the ureter, the best approach is through the Mayo posterior- 
lateral incision, the same incision as employed to explore the kidney. 




Reetu,s> 
toils cle-- 

and, 
sheath, 






Fig. 128. — Isolated ureter containing a stone. 

If the calculus is situated in the lower two-thirds of the ureter, the 
straight rectus incision gives the best exposure (Fig. 127), the exact 



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284 



E. S. JUDD 




Pe t vt o rh e "u/rro 



\\ " ^' 



Fig. 129. — Incision in ureter showing a stone. 



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REMOVAL OF STONES FROM THE URETER 



285 



position of the incision depending on whether or not the calculus is in 
the middle or lower third of the ureter. Under ordinary circumstances 
the operation should be performed without opening the peritoneum 
since less opportunity is allowed for infection. If the peritoneum is 
accidentally opened it should cause no alarm although care should 
be taken accurately to close it. Since the retroperitoneal space is 
opened by retracting the peritoneum away from the posterior muscles 
the ureter will probably retract with the flap of peritoneum so that 
the search for the ureter should be made on the posterior surface of the 
peritoneum and not on the anterior surface of the muscle. If the stone 



Sin 




Rectal 
skea-tk, 



PetvtorveuTru 



Uceter 






Fig. 130. — Interrupted catgut sutures being placed to close incision in ureter, 
do not pass through mucosa. 



Sutures 



is large the ureter is usually readily located by palpation. The great- 
est difficulty arises in locating a small stone in the lower end of a non- 
dilated ureter; fortunately this is the type of case most often relieved 
by conservative methods. Several years ago I called attention to a 
technic for exposing this part of the ureter and removing such stones. 4 
The operation consists in complete exposure of the lower end of the 
ureter in the manner employed in operating on the bladder for neo- 
plasm or diverticulum. The entire lower third of the ureter is brought 
into view (Figs. 128 and 129). After the stone has been removed it is 
best, I believe, loosely to close the opening in the ureter. Since Abell 



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£86 E. S. JUDD 

reported the series of cases in which he employed this technic I have 
used it many times without any ill-effects and, I am sure, that it has 
made convalescence much easier and shorter. The ureter has not 
healed in all cases without some drainage, but it has in many, and in 
others the urinary drainage was very slight. Stitching the ureter 
without penetrating the mucosa seems to be of distinct advantage. 



Table 1. — Patients with Ureteral Stones Operated on at the Mato Clinic 

1901-1918 Inclusive 

Total number 400 

Males 248 

Females 152 

Location: 

Right ureter 19? 

Left ureter 195 

Bilateral involvement 5 

Not stated S 



Table 2. — Age at Onset of Symptoms 

Cases 

0-10 years 10 

10-20 years 38 

20-80 years 129 

80-40 years 125 

40-50 years 61 

50-60 years 25 

60-70 years 8 

Average age 82.4 years 



Table 3. — Age op Patients on Entry to Hospital 

Cases 

0-10 years 4 

10-20 years 5 

20-30 years 87 

30-40 years 135 

40-50 years 108 

50-60 years 42 

60-70 years 12 

70-80 years 2 

Average age 37 7 years 



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REMOVAL OF STONES FROM THE URETER 287 

Table 4. — Dukation op Symptoms 

Cases 

1 year 138 

2 years 60 

S years 27 

4 years 23 

5 years 22 

5-10 years 62 

10-15 years S3 

15-20 years 19 

20-30 years 11 

Average duration of symptoms 4.8 years 

Patients entering hospital after symptoms of 1 year's 

duration 34 per cent 

Patients entering hospital after symptoms of 2 years' 

duration 49 per cent 

Table 5. — Pain Referred to 

Cases 

Region of kidney 281 

Right loin 123 

Left loin 142 

Both sides 16 

Lower abdomen 55 

Right 33 

Left 22 

Suprapubic region 5 

Upper abdomen 63 

Right 34 

Left 27 

Epigastric region 2 

Genitals 5 

Table 6. — Bilateral Kidney Patn 

Cases 

Stone in opposite ureter also 4 

Stone in opposite kidney also 5 

Pyelonephritis on opposite side 1 

Not determined 6 

Gro68 Hematuria 
71 cases 17.4 per cent 

Bladder Irritability 
129 cases 82 .1 per cent 



CONCLUSIONS 

1. The study of this series of 400 patients operated on for ureteral 
stone and the 126 patients treated by Braasch, leads us to conclude 



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288 E. S. JUDD 

that before instituting any method of treatment for the removal of 
stones from the ureter, it is well to bear in mind that a large percentage 
of such stones pass voluntarily; in the early cases, therefore, it is best 
to delay treatment. 

2. Unless there are definite contra-indications to non-operative 
treatment for the removal of the stones, an attempt should be made to 
remove them by non-operative methods. We doubt the advisability 
of attempting to remove stones from the middle and upper third of 
the ureter in this manner, but believe that with the development of 
the method nearly all small stones may be removed from the lower end 
of the ureter without operation. 



Table 7. — Urinalysis 

Cases 

Pus 102 

Blood 39 

Pus and blood 191 

332 (82.6 percent) 

Table 8. — X-ray Findings 

Cases 

Positive 295 (60 per cent) 

Negative 36 ( 9.0 per cent) 

Negative in 1919 11 ( 5.7 per cent of 193) 

Cybtoscopic Findings 

Definite obstruction to ureteral catheter 240 (60 per cent) 

No obstruction 109 (27 .2 per cent) 

Stone visible at meatus 1(1 per cent) 

Table 9. — Previous Operations 

Cases 

Ureteral stone, same side 3 

Ureteral stone, opposite side 1 

Renal stone, same side 4 

Renal stone, opposite side 1 

Negative renal exploration, same side 3 

Negative renal exploration, opposite side 1 

Nephrectomy, opposite side 5 

Nephrectomy, same side 2 

(Nephrectomy was done five and seven years before, but stone 

was left in the ureteral stump.) 

Bladder stone 2 

Appendectomy 54 

Other abdominal operations 68 

144 



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REMOVAL OF STONES FROM THE URETER 289 

3. While the operation for the removal of calculi from the ureter 
must be considered a major operation, it may be performed with prac- 
tically no mortality and with universally good results. Therefore, if 
there is a definite contraindication to non-operative treatment or if 
progress is not being made by such treatment, the stone should be 
removed by open operation without hesitation. 

Table 10. — Negative Explorations 

Cases 

Stone found in bladder 5 

Definite signs of stone found at operation (stone had probably 

passed before operation) 3 

Stone passed one month after operation with definite renal colic 

(stone probably in ureter but not located) 1 

Probable mistaken diagnosis 4 

Mistaken diagnosis in 1919 group of 193 cases 1 

Table 11. — Location of Stones 

( 'ases 

Ureteropelvic juncture 38 

Upper third of ureter 49 

Middle third of Ureter 7 

Iliac crest 4 

Lower third of ureter 198 

Ureterovesical juncture 53 

Intramural 34 

Table 12. — Bilateral Involvement 

Cases 

Bilateral ureteral 5 

Stone in same kidney 29 

Stone in opposite kidney 9 

Stone in bladder 1 

Table 13. — Duration op Symptoms before Nephrectomy for Ureteral Stone 

Cases 

1- 5 years 22 

5-10 years 11 

10-15 years 8 

15-20 years 

20-25 years 2 

25-30 years 2 

Average 8.5 years 

(16 of these patients had stone in the kidney also.) 

Mortality 

Case 216040: Operation, ureterolithotomy; patient died thirteen days after opera- 
tion; marked urinary extravasation was found. 
'19-19 



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290 E. S. JUDD 

Case 72640: Operation, combined ureterolithotomy and appendectomy; patient 
died of general peritonitis. 

Table 14. — Information Received in Answer to "Follow-up" Letters 

Operations since leaving the clinic 12 

For ureteral stone, opposite side 2 

For ureteral stone, same side 

For renal stone, opposite side 1 

For renal stone, same side 1 

Nephrectomy, same side 4 

(1 case complicated with nephrolithiasis) 

Nephrectomy, opposite side 1 

Negative renal exploration, same side S 

Stones passed since operation 31 

Stones passed previous to operation 48 (12 .3 per cent) 

Multiple stones (averaging 6) passed previous to operation . 9 

Letters received on an average of four and one-half years after 
operation stated that ureteral stone had occurred on the same side in 
3 cases, in 2 the first operation had been performed in the Mayo Clinic, 
and in one it had been performed elsewhere. 



BIBLIOGRAPHY 

1. Abell, I.: Surgery of the ureter. Louisville Month. Jour. Med. and Surg., 1907- 
1908, xiv, 6-12. 

2. Braasch, W. F. and Moore, A. B. : Stones in the ureter. Jour. Am. Med. Assn., 
1915, lxv, 1234-1237. 

3. Hunner, G. L.: The etiology of ureteral calculus. Surg., Gynec. and Obst., 
1918, xxvii, 252-270. 

4. Judd, £. S.: A method of exposing the lower end of the ureter. Ann. Surg., 
1914, lix, 393-395. 

5. Lewis, B.: Presentation of a patient, the subject of calculous formations in the 
kidney, ureter, and bladder; the kidney inactive; removal of the stones from the only 
active kidney by nephrotomy, and from the bladder by means of the operative cysto- 
scope. St. Louis Med. Rev., 1903, xlviii, 433-435. 

6. Lewis, B.: Some new instruments in operative cystoscopy. Jour. Am. Med. 
Assn., 1918, lxxi, 1797-1799. 

7. Mayo, W. J.: The incision for lumbar exposure of the kidney. Ann. Surg., 
1912, lv, 63-65. 

8. Rovsing: Erfahrungen fiber Uretersteine. Monatschr. f. Urol., 1901, vi, 385: 
Quoted by Hunner. i 



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SURGERY OF THE URINARY BLADDER* 

E. S. JUDD 



The bladder, situated beneath the pubic bones, is not so accessible 
for surgical intervention as the other abdominal viscera. Instead of 
being covered 1 y a layer of protective peritoneum it is almost com- 
pletely encased in a fatty tissue which offers little if any resistance to 
infection. The inaccessibility of the organ and the difficulty in pre- 
venting infection are the sources of trouble in surgery of this region. 
However, the functional results obtained even after extensive opera- 
tions are very gratifying. 

It is possible to remove a large segment of the wall and still main- 
tain practically normal functional conditions. Urine enters the blad- 
der by spurts and jets under the influence of a small sphincter muscle 
at the ureterovesical juncture, although this tiny muscle may be 
sacrificed in one or both meatuses without serious consequences; 8 the 
only difference is that the urine enters the bladder in a continuous 
stream. In a large series of cases lesions requiring surgical interven- 
tion at or near one of the ureteral orifices have made it necessary to 
sever the ureter and reimplant it into another segment of the bladder. 
By follow-up letters to patients it has been found that the kidney was 
functionating normally years afterward without infection or hydro- 
nephrosis. 

Our experience is now sufficient to enable us to assert that while 
severing and reimplanting the ureter offers some additional risk, it is 
not sufficient to contra-indicate the procedure if by it a better ultimate 
result can be obtained, as in cases in which malignancy is suspected. 
If transplantation makes recurrence less likely, it certainly should 
be done. Severing and transplanting both ureters at the same time 
offers only the additional mechanical difficulty of implanting the 

* Presented before the Montana State Medical Society, Billings, July, 1919. 
Reprinted from Journal-Lancet, 1920, zl. 6-9. 

291 



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292 E. S. JUDD 

ends of the ureters free enough to insure their remaining open during 
the period of healing, with the consequent swelling and edema. We 
have successfully reimplanted both ureters in several instances. 

In certain cases the end of the ureter may be involved in the malig- 
nant process so that when the disease is thoroughly removed the 
ureter is not of sufficient length satisfactorily to be implanted in the 
bladder. In such cases we now ligate the ureter and allow it to 
drop back into the wound. This procedure was adopted with much 
trepidation. Our first case was that of a patient on whom a great deal 
of operating had just been done and either nephrectomy or intestinal 
transplantation was out of the question. We thought that it would 
be necessary to remove the kidney within a few days; however, it was 
not necessary, nor has it been in subsequent cases. The ligation of 
the ureter has not appeared to add greatly to the seriousness of the 
situation. We do not hesitate, therefore, to ligate the ureter when- 
ever the necessity arises and when we are sure that the opposite kidney 
is in good condition and is functionating. 

In resections of the bladder for a lesion at and obstructing the end 
of the ureter with a hydroureter I believe it is probably as safe to ligate 
the ureter as to implant it. Just what occurs in the parenchyma 
and pelvis of the kidney when the ureter is ligated has not been defi- 
nitely determined and cannot be worked out satisfactorily by animal 
experimentation. We have ligated the ureter many times during the 
course of operations and we have not found a resulting hydronephrosis 
although we have followed some of these cases for a long time, while 
in all the animals on which the operation has been done a hydroneph- 
rosis occurred. 

Weld has recently endeavored to determine the results of ligating 
the ureter in animals. He filled the kidney pelvis with a solution which 
shut out the x-rays as soon as the ureter was ligated; then frequent 
exposures of the kidney were made extending over a considerable 
period of time. He thought that by watching the outline of the 
kidney pelvis he could discover any tendency toward hydronephrosis. 
After the ureter had been ligated and the pelvis distended in this 
manner, however, no change in the shape of the pelvis could be demon- 
strated, but the salt solutions introduced into the kidney pelvis under 
these conditions were very quickly absorbed. For instance, phenol- 
sulphonephthalein left in the pelvis after ligation of the ureter appeared 
in the urine from the other kidney in a very few minutes. Such find- 



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SURGERY OF THE URINARY BLADDER 293 

ings should be of great importance in convincing us of how readily 
infection, which gets into the kidney pelvis, may be generally dis- 
tributed. Undoubtedly when the ureter in man is ligated the back 
pressure from the secieted urine is equal to or greater than the blood 
pressure in the kidney so that the blood is very soon shut out of the 
kidney and it ceases to functionate and becomes practically scar 
tissue. Ligation of the ureter in a dog is apparently always followed 
by a hydronephrosis, and this may increase in size, rupture, and cause 
death. It was at first assumed that this difference might be caused 
by the kidneys receiving a blood supply through the capsule after the 
renal vessels had been compressed. In order further to study this 
condition in several experiments we ligated the ureter and stripped 
the capsule from the kidney and it seemed to us that the same degree 
of hydronephrosis developed in the kidneys from which the capsule 
had been removed as in those from which it was not removed after 
ligation of the ureter. 

It has recently been established in experimental work on animals 
and it has practically been established in man (Caulk and Fisher), 
that the ureter may be occluded for a number of days (the longest time 
about fourteen days); if the lumen of the ureter is re-established the 
kidney will gradually begin to functionate and will usually return to 
its normal function. We have had a similar experience although the 
conditions differ slightly. The ureter had been completely blocked 
for at least six days by a stone, and the kidney functionated within 
a few days after removal of the stone. The fact that the kidney will 
survive and re-establish its function even after the ureter has been 
occluded for some time, should be remembered in connection with the 
traumatization of the ureters which occasionally occurs in extensive 
pelvic operations. 

At least one half the bladder may be removed and good function 
obtained. It has been suggested that these small bladders gradually 
increase in size until they are normal; if a very large segment is re- 
moved, however, it is probable that the size will remain diminished as 
is evidenced by frequency of urination. 

The most important consideration in surgery of the bladder is the 
preservation of the sphincter muscle at the urethral orifice. This is 
necessary if the patient is to maintain any degree of comfort. If the 
question arises of whether or not the sphincter is to be sacrificed it is 
best to view the condition as inoperable for the patient will practically 



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294 E. S. JUDD 

never be satisfied without urinary control. The only alternative is 
to reimplant the ureters into the intestinal tract, a satisfactory pro- 
cedure in many cases as the rectal sphincter will control the urine. 

In operating for the unfortunate condition known as bladder 
exstrophy it has been our plan for a number of years to reduce the 
prolapsing bladder to the abdomen by some plastic measure and to 
maintain it there by closing over the wall. These operations have 
been successful mechanically, but they are not satisfactory from the 
patient's standpoint as he has no better control of urine than before. 
In these cases also since there is no sphincteric control it is best to 
transfer the ureters to the colon, depending on the rectal sphincter 
to control the urine. C. H. Mayo has shown that this control is 
very often satisfactory. The objection to it is the possibility of in- 
fection ascending from the intestinal tract by way of the ureter to 
the kidney, which has undoubtedly occurred in many cases. How- 
ever, with the technic of implantation of the ureter suggested by 
Coffey and by Stiles, the likelihood of severe ascending infection has 
been greatly reduced. The operation is a serious procedure, but it 
improves the condition more than any other. 

Another extremely interesting anomaly is the extra vesical opening 
of the ureter. The ureter may open into the vagina or into the uterus. 
It may be the only ureter on that side or the two ureters may be pres- 
ent in their normal positions with an additional ureter on one side open- 
ing extravesically. In these cases the history usually shows that 
there has always been more or less urinary incontinence. Sometimes, 
apparently, the ureter closes for a time, then opens and drains again. 
In our experience, this condition has been found more frequently in 
girls and is recognized by the fact that in addition to the normal uri- 
nation there is a persistent incontinence. It is often difficult to locate 
the extravesical opening. The condition is rare and may easily be 
overlooked or thought to be sphincter incontinence, a condition which 
practically never occurs in young women. 

Diverticulum of the bladder undoubtedly is very often congenital. 
The condition is being recognized much more frequently than formerly 
and is probably the cause of many cases of protracted cystitis, especial- 
ly those associated with obstruction caused by the prostate. Di- 
verticula are very satisfactorily treated surgically. 

Foreign bodies are frequently found in the bladder. 6 It is of in- 



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SURGERY OF THE URINARY BLADDER 295 

terest to note that a foreign body, such as a piece of bone from an 
osteomyelitis, or a piece of metal which had been thrust into the soft 
tissues above the buttocks, may gradually work its way into the 
bladder without producing symptoms of urinary soiling in the tissues. 

The etiology of the formation of bladder stones and the frequency 
of their recurrence in certain persons is undoubtedly due to some 
type of infection. The risk of removing stones in old persons is not 
due to the operation itself, but to poor resistance and the existing 
infection ; with a stone in the bladder, the kidney function is likely to 
be reduced. 

Rupture of the bladder is a frequent occurrence, but if the con- 
dition is recognized and treated early, all the patients get well. Often 
the rupture extends into the peritoneal cavity and it is necessary to 
sponge out the urine. This type of peritonitis, however, is rarely fatal. 
Operation is indicated in any case of bladder rupture, no matter how 
late it is recognized. 

A very unfortunate injury is that of fracture of the pelvis and the 
tearing away of the neck of the bladder and the urethra. I have not 
had a great deal of experience with such cases at the time of the in- 
jury, but I believe that more attention should be paid to establishing 
some sort of a urethra immediately. If -scar tissue is allowed to form 
after the injury, it is almost impossible later to develop any kind of 
urethra. We see many patients in this condition each year, and while 
the urethra may be forcibly dilated a satisfactory result is seldom 
obtained even after several years of treatment. In instances in 
which I have seen the patient early, I have been able to penetrate 
the traumatized tissue and establish a urethra at once. 

Inflammation of the bladder alone is not common, but inflamma- 
tion in the bladder in conjunction with the same process in the kidney 
or other parts of the tract is common. 

Tuberculosis never occurs in the bladder alone although it is present 
in most cases of tuberculosis of the kidney. Cystitis, which was 
formerly considered common is now an unusual occurrence except as a 
part of an infection in some other part of the genito-urinary tract. The 
same general statement may be made concerning ulcerations in the 
bladder. The submucous ulcer, a condition described by Hunner, is 
being widely discussed. It may occur as a very small lesion in the 
mucosa and then become an extensive edema in the submucosa and 
muscularis. There are no urinary changes. The symptoms are ex- 



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296 E. S. JUDD 

treme irritability and frequency. It is difficult to recognize the 
condition as the findings are slight. The differential diagnosis lies 
between a submucous ulcer and the bladder symptoms of a neu- 
rasthenic. 

The surgery of vesical neoplasms 6 has not been altogether satis- 
factory. Fulguration undoubtedly has helped in the treatment of 
small papillomas, but, on the other hand, it has not always been 
judiciously used and many patients who might have been operated on 
satisfactorily have lost that chance by continued fulguration which 
was of no benefit. 

Cancers of the bladder should not be fulgurated, and in any type 
of case in which fulguration does not promptly relieve operation should 
be done. Operation is of great benefit in cases of early malignancy of 
the bladder, but there is not much to be derived from extensive opera- 
tion after the growth has penetrated the wall of the bladder. 

In operating for tumors of the bladder it is necessary to make a 
large incision in order to obtain sufficient exposure and to remove the 
prevesical tissues widely with the bladder wall. The transperitoneal 
operation is necessary only in those cases in which the growth is on 
or close to that portion of the bladder. 

Operations on the bladder, especially for bladder tumors, must 
be done in the same manner in which the operations for neoplasms 
of the stomach and intestines are done. The principles of general 
surgery must be employed in this field, with the same surgical judg- 
ment and technic, if the good results secured elsewhere are to be 
obtained here. 



BIBLIOGRAPHY 

1. Caulk, J. R. and Fisher, R. ¥.: Experimental study of the effect of ureteral 
ligation with particular reference to its occlusion during pelvic operation. A prelimina- 
ry report. Tr. Am. Assn. Genito-Urinary Surgeons, 1915, x, 72-81. 

2. Coffey, R. C: Physiologic implantation of the severed ureter or common bile 
duct into the intestine. Jour. Am. Med. Assn., 1911, lvi, 397-403. 

3. Draper, J. W. and Braasch, W. F.: The function of the ureterovesical valve. 
Jour. Am. Med. Assn., 1913, lx, 20-27. 

4. Hunner, G. L.: Elusive ulcer of the bladder. Further notes on a rare type of 
bladder ulcer, with a report of twenty-five cases. Am. Jour. Obst., 1918, lxxviii, 
374-395. 

5. Judd, E. S.: Foreign bodies in the urinary bladder. Jour.-Lancet, 1916, xxrvi, 
474-477. 



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SURGERY OF THE URINARY BLADDER 297 

6. Judd, E. S. and Harrington, S. W.: Tumors of the urinary bladder. South. 
Med. Jour., 1918, xi, 129-139. 

7. Mayo, C. H.: Exstrophy of the bladder and its treatment. Jour. Am. Med. 
Assn., 1917, Ixix, 2079-2081. 

8. Stiles, H. J.: Epispadias in the female and its surgical treatment. Surg., Gynec. 
and Obst., 1911, xiii, 127-140. 

9. Weld, E. H. : Renal absorption with particular reference to pyelographic medi- 
ums. Med. Clin. North \m., 1919. iii, 71^-731. 



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SECONDARY MELANO-EPITHELIOMA OF 
THE BLADDER* 

C. G. RICHARDS 

Melano-epithelioma is always primary in the eye or in pigmented 
moles of the skin, and it metastasizes so rapidly that the patient suc- 
cumbs soon after the appearance of the growth. The extreme rarity 
of its occurrence in the bladder seems to warrant the report of the 
clinical history and subsequent course of the disease in a case under 
our observation. Mention has been found in the literature of but one 
similar case. 1 The history of our patient is as follows: 

Case 218587. — A man, aged 45, stated that his mother had died of 
cancer of the stomach at the age of 73, and, like himself, had had 
pigmented moles irregularly distributed over the entire body. For 
the past five or six years the patient had noticed that a rather large 
mole situated on the right side of the abdomen near the umbilicus had 
a core of granular debris which could be expressed, and two months 
previous it had begun to enlarge and had a tendency to bleed. Be- 
cause of the bleeding the patient consulted his physician who excised 
the growth. Histologic examination revealed melano-epithelioma. 
Further surgical advice was sought. The examination was negative 
except for slight enlargement of the inguinal lymph nodes. The 
urinary findings were negative. A gland removed from the groin 
was found to be malignant and therefore all the lymphatic glands 
in both groins and Scarpa's triangle were removed; the external 
saphenous vein was ligated. While the patient was convalesing 
from the operation radium treatment was begun, and was continued 
at frequent intervals. Eight months later another small gland in 
the inguinal region was discovered, which proved to be of the nature 
of those previously removed. Ten months later increased frequency 
of urination and diminution in the size of the stream, and nocturia 

* Reprinted from Surg. Gynec. and Obst., 1919, xxix, 266. 

298 



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SECONDARY MELANO-EPITHELIOMA OF THE BLADDER 299 

were noticed. The urine contained a number of erythrocytes and 
pus-cells. 

On cystoscopic examination multiple areas of black rounded tumors 
varying in size from % to to 5 cm. were found on the right base of the 
bladder anterior to the right meatus. On the left wall two of the 
tumors had pedicles; the other were sessile. 

As soon as the bladder condition was discovered the intravesical 
radium treatment was instituted. To the present time 400 mg. 
hours have been given. At the last cystoscopic examination one 
month ago no material change was noticeable except perhaps a slight 
increase in the size of one or two of the tumors. 

BIBLIOGRAPHY 

1. Targett, J. H.: Secondary melanotic sarcoma of the bladder. Tr. Path. Soc, 
Lond., 1890-1891, xlii, 214-215. 



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DIVERTICULA OF THE POSTERIOR URETHRA* 

H. C. BUMPUS 

The repeated finding of diverticula of the posterior urethra during 
routine cystoscopic examination led to a search through our records 
and the literature for similar cases. As was expected, few were found. 

The literature, as reviewed by Ehrlich, revealed but 70 cases of 
urethral diverticula up to 1908. Watts reported one case and reviewed 
the literature in 1906, and Englander added 2 cases in 1917. In our 
cases the diverticula were all confined to the posterior urethra; their 
clinical histories vary considerably from those reported in the litera- 
ture. 

Watts, besides his complete and thorough review of the literature, 
gave an excellent classification of urethral diverticula which we have 
adopted : 

A. Congenital diverticula. 

B. Acquired diverticula. 

1. From dilatation of urethra due to 

a. Calculus. 

b. Stricture. 

2. With perforation of urethra resulting from 

a. Injuries to the urethra. 

b. Rupture of abscesses into the urethra. 

c. Rupture of cysts into the urethra. 

A differentiation is also made between true and false diverticula. 
The former is a dilatation of the normal urethra with a mucous mem- 
brane lining identical with that part of the urethra from which it arises. 
The latter is the result of urethral rupture and, therefore, has a lining 
of epithelium or fibrous tissue according to the extent of repair that 
has occurred. Of the true diverticula the congenital offers the most 
perfect type. It occurs in the anterior urethra and is probably the 
result of a failure of the urethral floor to close during fetal life, a con- 

* Reprinted from Surg. Gynec. and Obst, 1919, xxix, 388-392. 

300 



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DIVERTICULA OF THE POSTERIOR URETHRA 301 

dition similar to that of hypospadias, or, as Watts suggests, a condition 
due to congenital stricture or phimosis. 

Diverticula of the posterior urethra are probably always of the 
acquired type and usually traumatic in origin. Surgical procedures 
about the perineum either for the drainage of the seminal vesicles, 
as in Case 1, or for the removal of the bladder or prostatic stones, as in 
Case 4, are probably the most frequent factor in their formation. 
Frequently the falling astride some hard object with resulting rupture 
of the urethra or the formation of a hematoma with secondary rupture 
into the urethra results in their formation. Strictures are also an 
etiologic factor, both because of their tendency to cause dilatation 
posteriorly and because of the inaccurate passage of sounds in an 
attempt to dilate with resulting false passage and urethral rupture. 
Abscess formations in the neighborhood of the posterior urethra or 
in the seminal vesicles, as in Case 3, with secondary rupture and 
drainage into the urethra are frequently the origin of diverticula. 

In cases in the literature a tumor at some point along the urethra 
is an almost constant finding, and the history of being able, by digital 
pressure, to express varying amounts of urine from such a mass is 
considered very suggestive. In our series but one patient (Case 4) 
gave such a history. This fact seems most pertinent, as our illustra- 
tions show to what size such diverticula may develop and yet give 
no physical signs; they even burrow under the bladder until they 
nearly equal it in capacity (Fig. 135). Lane reported several cases 
similar in character, found at necropsy, and Isaacs reported one that 
caused death by rupturing into the peritoneal cavity with resulting 
peritonitis. 

Diverticula of the posterior urethra give a series of symptoms 
which are the result of a chronic inflammatory process going on in 
close proximity to the sphincter musculature and involving the 
urethra itself: (1) Dribbling or complete incontinence, depending 
on how near the diverticulum is to the external sphincter, and to the 
extent it has become involved in the inflammatory tissue produced 
by it; (2) dysuria resulting from the passage of urine through a con- 
stantly inflamed and irritated posterior urethra producing pain and 
scalding often accompanied by tenesmus; and (3) the presence in the 
perineum of a pocket filled with infected residual urine causing a 
constant feeling of discomfort often described as "resembling a ball 
of fire,*' which compels frequent urination in an effort to relieve. 



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302 H. C. BUMPUS 

That such diverticula may be overlooked is easily understood if 
it is realized that the condition is often associated with a normal 
bladder, as it was in 3 of our cases. Unless an endoscope or a direct 
cystoscope is used, the floor of the posterior urethra may be over- 
looked. In Case 1 a cystoscopic examination had been made previous 
to our examination, and the patient was told that conditions were 
normal. 





Fig. 131. — Lead catheter coiled in a di- Fig. 132. — Bullet and fragments lodged 

verticulum of the posterior urethra behind the symphysis pubis, and lead 
(Case 1). catheter inserted into the diverticulum 

(Case 2). 

The etiologic factors in 3 of our 4 cases were the result of 
former operations for the drainage of infected tissue; in the other 
2 the result of spontaneous drainage of abscesses into the urethra. 

Case 1. (263163), C. E. M., a single man, aged 33, was admitted to 
the clinic March 12, 1919. The patient had had gonorrhea four 
years before, and operations as follows: Drainage of seminal vesicles 
in 1917, followed by repeated injections of the epididymis on both sides 
with silver salts; appendectomy June, 1918, and cystostomy December, 
1918. He complained of dribbling and frequency. Following the 
neisserian infection he had tried various forms of treatment without 
result, and finally had had both seminal vesicles drained with complete 
relief for three months, when the old symptoms of dysuria, frequency, 
and perineal pain returned, together with extreme nervousness, loss 
of weight, weakness, and nausea. His appendix was removed at 



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DIVERTICULA OF THE POSTERIOR URETHRA 



303 



this time, and six months later cystostomy with bladder drainage 
was done, both without relief. 

Physical examination disclosed bilateral thickening of the epi- 
didymis and of the left vesicle. Analysis of a twenty-four hour 
specimen of urine showed 900 c.c. with specific gravity of 1030, acid 
in reaction, a trace of albumin, no sugar, an occasional red blood 
cell and large amounts of pus. The phenolsulphonephthalein test 





Fig. 133. — Lead catheter inserted into 
diverticulum filled with thorium; bullet 
fragment lodged behind symphysis. 



Fig. 134. — Similar to Figure 133; the di- 
verticulum is filled with thorium, dis- 
closing its extent and relation to the 
bladder, which is filled with silver iodide. 



of the kidney function showed a 60 per cent return of the dye in 
two hours. X-rays of the kidneys, ureters, and bladder were negative. 
The systolic blood pressure was 130; the diastolic 90. 

Cystoscopic examination revealed a normal bladder with clean 
urine coming from each meatus and a normal internal urethral 
sphincter. In the posterior urethra just anterior to the verumontanum 
was an opening into a diverticulum filled with phosphatic deposit 
and pus. A lead catheter was coiled in the diverticulum (Fig. 131).' 

Operation was advised, as we believed that diverticulum in this 
position, by keeping up a constant source of inflammation about the 
external sphincter and in the posterior urethra, would account for 
the dribbling and dysuria, and that it probably was a large factor in 
the causation of the patient's extreme nervousness. 



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304 H. C. BUMPUS 

Case 2. (193464), W. C. S., a married man, aged 36, registered 
at the clinic May 8, 1917. The patient had had a slight neisserian 
infection of two weeks duration in 1901, appendectomy in 1900 and 
an exploration and drainage of the perineum following a rifle bullet 
wound in 1903. From the date of this wound, when a 22 caliber 
bullet entered the perineum and lodged behind the symphysis (Fig. 
132), he had had constant pain in the bladder; the urethra discharged 
pus. The pain was e&caggerated when the bladder was full or the ab- 
domen was distended; it radiated to the glans penis during micturition. 




Fig. 135. — Cystogram of bladder and of Fig. 136. — Lead catheters coiled in di- 

divertieulum of the posterior urethra verticula of the posterior urethra 
(Case 3). (Case 4). 

Physical examination was negative except for a right inguinal 
hernia, a perineal scar, and a urethral discharge. The analysis of a 
twenty-four specimen showed 700 c.c, a specific gravity of 1020, 
alkaline reaction, a slight trace of albumin, no sugar, and a large 
amount of pus. The blood examination showed a negative Was- 
sermann, hemoglobin of 77 per cent, 4,500,000 red blood cells, and 
6800 white blood cells. Repeated smears of the urethral discharge 
showed many pus cells but no characteristic Gram-negative diplococci. 
X-rays of the kidneys, ureters, and bladder were negative except 
for the presence of the rifle bullet and its fragments (Fig. 132). 

Cystoscopic examination showed a normal bladder with clear 
urine coming from each meatus. The internal urethral sphincter 



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DIVERTICULA OF THE POSTERIOR URETHRA 305 

was normal. In the posterior urethra to the right of the verumon- 
tanum was an opening into a diverticulum. Into this a lead catheter 
was inserted (Fig. 133) . The diverticulum was then filled with thorium. 
Figure 134 shows the extent and position of the diverticulum in relation 
to the bullet fragments. The diverticulum was evidently the result 
of the bullet wound, or of the subsequent drainage of the wound, and 
accounts fully for the painful urination and constant urethral discharge. 




Fig. 137. — Diverticula of posterior urethra filled with thorium, and the bladder filled with 
silver iodid. showing lax atonic bladder and the relative position of the two diverticula. 



Case 3. (214557), F. B., a married man, aged 40, came for ex- 
amination Nov. 21, 1917. The patient's history was negative except 
for an axillary abscess seven years before. Following an attack of in- 
flammatory rheumatism four years before, he commenced to have 
attacks of dysuria which became more and more frequent and were 
accompanied by frequency and nocturia, all of which grew progressively 
worse until four months before, when he was obliged to wear a urinal. 
The passage of urine was attended with great pain and scalding. 
During the past four years he had lost much weight and strength; 
he complained of frequent night sweats and chills. 

Physical examination revealed many signs of old tuberculous 
processes in the lungs, and a bar of hard, firm, inflammatory tissue 
about 4 inches up in the rectum. A twenty-four hour specimen of 
urine, 1550 c.c, gave a specific gravity of 1009, alkaline reaction, a trace 

•19—20 



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306 II . C. BUMPUS 

of albumin, no sugar, many red blood cells, and much pus, stained 
specimens of which failed to show tuberculosis bacilli. Four guinea 
pigs were injected with specimens of bladder urine obtained on dif- 
ferent days and at necropsy one pig showed miliary tuberculosis 
foci throughout the peritoneum. The phenolsulphonephthalein test 
oi kidney functions showed a 35 per cent, return of the dye in two 
hours. X-rays of the kidneys, ureters, and bladder ^ere negative; 
x-ray of the chest showed calcified pleurisy at left base and a healed 
focus of tuberculosis at right apex. 

Cystoscopic examination showed a chronic inflammatory tuber- 
culous type of bladder with many areas of granulation tissue and 
cicatricial changes involving the internal sphincter, which was com- 
pletely relaxed. On the floor of the posterior urethra just anterior 
to the verumontanum was an opening into a diverticulum about 3 cm. 
in diameter. This, together with silver iodid and a cystogram (Fig. 
135), shows the diverticulum to be nearly equal in size to the bladder. 
The diverticulum probably was primarily an abscess in one or both 
vesicles which ultimately ruptured into the urethra. While the 
abscess cannot alone be considered the cause for all the present urinary 
symptoms, since the bladder is so extensively involved, it may well 
be the etiologic origin of them. 

Case 4. (26573, R. L. C, a married man, aged 49, came to the 
clinic April 1, 1919. The patient had had an operation for multiple 
bladder and prostatic stones in 1910. He complained of incontinence 
and perineal pain, and of always having had great difficulty in empty- 
ing his bladder, which seemed to lack musculature. Often he was 
obliged to double himself up and exert pressure suprapubically in 
order completely to empty the bladder. In 1907 marked bladder 
irritability commenced, accompanied by dysuria and frequency. 
In 1910 the perineal operation was performed, and following this 
sphincter control was lost and he was obliged to wear a urinal. He 
has also had some difficulty in the control of gas and feces if the bowels 
are loose. 

Physical examination showed a well-developed man of 196 pounds, 
having a systolic blood pressure of 160, and a diastolic of 100. A. 
transverse perineal scar, and faulty closure of the arches of the sacrum 
were noted, which the x-ray demonstrated to be a spina bifida occulta. 
A twenty-four hour specimen of urine showed a specific gravity- 



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DIVERTICULA OF THE POSTERIOR URETHRA 307 

of 1020, alkaline reaction, a trace of albumin, no sugar, an occasional 
red blood cell, and much pus. Blood examination showed 24 mg. 
of blood urea pus in 100 c.c. of blood. The Wassermann test was 
negative. X-rays of the kidney, ureters and bladder were negative. 
Neurologic examination revealed a saddle anesthesia. 

Cystoscopic examination showed a large atonic and trabeculated 
bladder with chronic diffuse cystitis and a relaxed sphincter. In 
the posterior urethra at either side of the verumontanum were the 
openings of two diverticula filled with pus and phosphatic deposit. 
The openings were large enough to permit the coiling of catheters in 
both at one time, thus giving the impression of a single diverticulum 
rather than two (Fig. 137). A second plate was made, the bladder 
having in the meantime been filled with silver iodid, in order to obtain 
a better idea of the relative position of the diverticula in relation to 
the bladder (Fig. 137). The diverticula in this case are clearly the 
cause of the perineal discomfort and explain the expressing of urine 
by perineal pressure. They are undoubtedly a result of the operation 
for the .removal of bladder and prostatic stones. 

CONCLUSIONS 

1. Diverticula of the posterior urethra are generally of the acquired 
type. 

2. Probably the most frequent etiologic factor is a previous 
perineal operation. 

3. They give rise to a definite syndrome, namely, incontinence, 
dysuria, interrupted micturition, perineal pain, and pyuria. 

4. The absence oi a perineal tumor is not incompatible with their 
presence. 

5. Since they may be associated with a normal bladder they may 
be easily overlooked unless the posterior urethra is carefully examined. 

BIBLIOGRAPHY 

1. Ehrlich: Zur Kasuistik und Behandlung der Divertikel der mannlichen Harn- 
rbhre. Beitr. z. klin. Chir., 1908, lix, 198-205. 

2. Englander , S. : Diverticulum of the urethra. Jour. Am. Med. Assn., 1917, 
Ixviii, 851-354. 

3. Isaacs: New York Jour. Med., 1858, 3 s., v, 9: Quoted by Watts. 

4. Lane, W. A. : Compound diverticulum in connection with the prostatic urethra. 
Tr. Path. Soc., Lond., 1884-1885, xxxvi, 288-289. 

5. Watts, S. H.: Urethral diverticula in the male. Johns Hopkins Hosp. Rep., 
1906, xiii, 49-89. 



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THE TREATMENT OF URETHRAL CARUNCLE* 

J. L. CRENSHAW 

The varied and often unsatisfactory treatment of urethral carun- 
cles and the high percentage of recurrence after their removal 
led us to study these growths and the best methods of removing them. 

A review of the histories of patients with urethral caruncle who 
have been referred for examination to the cystoscopic department 
of the Mayo Clinic during the past four years (April 29, 1915 to 
June 1, 1919) showed that the symptoms most frequently complained 
of were urinary frequency, pain and burning on urination, soreness 
around the meatus, tenesmus, and bleeding. A few patients had no 
symptoms referable to the caruncle. Cystoscopy was done on all 
patients with a history of urinary trouble; the findings were usually 
negative. The nervousness which is a symptom in mast of these 
cases is unquestionably due, in many instances, to the constant irrita- 
tion in the urethra, since it disappears as soon as the caruncle is 
removed. In other cases, the nervous symptoms are independent of 
the caruncle since they persist after its removal. In many instances 
the inconvenience and suffering seem so out of proportion to the size 
of the caruncle, that it is often overlooked as the cause of the trouble. 

The cases of urethral caruncle observed at the clinic make it 
possible to draw but one definite conclusion with regard to the etiology. 
Urethral caruncles seem to be secondary to a chronic irritation or 
ulceration of the urethral mucosa. Some observers have attributed 
caruncles to the gonorrheal type of chronic urethritis following directly 
on gonorrheal ulcerations. The bursting of retention cysts of Skene's 
glands has also been considered a cause (Englisch). It is probable 
that chronic irritation from many different causes plays a part in their 
formation. 

•Presented before the Southern Minnesota Medical Association, Rochester, June, 
1919. 

Reprinted from Minn. Med., 1920, iii. 54-57. 

308 



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THE TREATMENT OF URETHRAL CARUNCLE 



309 



Pathologically, urethral caruncles are of papillomatous outline 
with either a broad or narrow base growing from the posterior or 




Fig. 138. — Exposure of urethral meatus showing urethral caruncle with a single mass 

on the posterior wall. 

lateral walls of the urethra just inside the meatus. I have found only 
one case of a caruncle on the anterior wall reported in the literature 
(Neuberger). These growths vary in color from yellowish gray to 




Fig. 139. — Exposure of urethral meatus showing urethral caruncle with posterior 

and lateral masses. 

bright red. Often acute inflammation of the anterior portion of 
the urethra and tissues surrounding the meatus renders the whole 
area exquisitely sensitive. Grossly, differential diagnosis of urethral 



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310 



J. L. CRENSHAW 



caruncle and hemorrhoidal growths, urethral cysts, fibromas, pro- 
lapse of the urethral mucosa, and malignant growths is often difficult ; the 





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Fig. 140. — Operative technic. Caruncle raised with pick-up forceps and ready to be 

seized by clamp. 

microscopic findings, however, are characteristic, showing the urethra 
caruncles to be of a uniform structure, composed of loose connective tis 
sue permeated by numerous blood vessels which are often much dilated 




Fig HI. — Operative technic. Caruncle seised in clamp and about to be severed with 

scissors. 

The growth throughout shows marked inflammation, and is infiltrated 
with mononuclear and polynuclear leukocytes. Many plasma cells 
are found, especially surrounding the blood vessels. Toward the 



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THE TREATMENT OF URETHRAL CARUNCLE 311 

free surface the blood vessels are newly formed. The growth is 
covered by the usual urethral epithelial layer which in areas is thinned 




Fig. 142. — Operative technic. Cauterization of stump before removing clamp. 

out or absent, leaving an easily bleeding ulcer. Virchow speaks of 
the normal folds of the urethral meatus as caruncles, designating what 
we know as caruncles by the term "vascular polyps." 




Fig. 143. — Narrow cauterized stump after removing clamp. 

Some authors have reported a malignant incidence as high as 25 
per cent in the original caruncle and many malignant recurrences. 10 
We have not seen a case of malignant recurrence, probably because 
of the fact that by our method the tissue removed is saved for micro- 



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312 J. L. CRENSHAW 

scopic examination, and early radical operation is done in all cases in 
which microscopic section has demonstrated malignancy in the 
original growth which grossly could not be distinguished from the 
usual benign caruncle. 

In reviewing the literature on urethral caruncle, I find that the 
removal of these growths has been advised by such methods as ex- 
cision, actual cautery, various caustic acids, and high frequency 



Fig. 144 (Case 169585). — Section of caruncle showing the general outline of the growth 

at low magnification. 

current. 1 , 3 , 4 , 6 , 7 , 9 Most articles record the fact that a recurrence is 
frequent and with it a recurrence of the original symptoms. 

Recurrences have been divided, on the basis of our experience, 
into two classifications: First, true recurrence of the caruncle due to 
incomplete removal of the base, and second, prolapse of the mucous 
membrane of the urethra due to the contraction of the scar following 
the removal of the original caruncle. The majority of so-called 
recurrences belong to the prolapse group; they involve a portion or 
all the circumference of the urethra proportionate to the extent of the 



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THE TREATMENT OF URETHRAL CARUNCLE 



313 



original scar. A removal of this prolapse by any method merely 
results in a larger scar and in a repetition of the prolapse. We have 
seen several cases following removal of a caruncle and subsequently 
repeated removals of prolapsed mucosa in which the mucosa of the 
trigone was dragged down into the urethra and even protruded from 
the meatus. The many patients with recurrences of the second type, 
prolapse of the mucosa, who have consulted us and for whom permanent 




«& 







Fig. 145 (Case 169585). — Caruncle showing the characteristic structure and epithelia 

covering. ( X50.) 

relief was impossible led us, four years ago, to adopt our present form 
of procedure which has proved very satisfactory. The steps in the 
method are as follows: 

1. The patient is placed in the lithotomy position, and the parts 
are thoroughly cleansed with soap and water. A swab of cotton on 
a toothpick saturated in 10 per cent cocain solution and lubricated 
with a soluble lubricant is inserted into the urethra and left for ten 
minutes. 



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314 



J. L. CRENSHAW 



£. The labia are separated by an assistant. On examination 
the caruncle is found to consist either of a single tag on the post- 
erior wall or of posterior and lateral masses. Each tag is picked up 
with a small Graefe fixation forceps and clamped off in the long axis 
of the urethra with a special clamp which has a broad blade and a 
narrow crushing edge. Care is taken to include in the bite all the 
caruncle and none of the submucosal structure of the urethra. 




Fig. 146 (Case 169585).— Section of caruncle shown in Figure 145. (X100). 

3. The growth is cut off close to the upper surface of the clamp; 
the crushing of the pedicle prevents all bleeding and makes an ac- 
curate removal possible. The specimen is saved for microscopic 
study. 

4. The cut surface is thoroughly seared with acid nitrate of mer- 
cury solution applied with a wooden applicator. An excess of the acid 
to run over the blades of the clamp and cauterize other areas of the 
urethral mucosa is cautiously avoided. 

All tags are removed in the same manner; when removal is complete 
one or more narrow longitudinal white lines about 1 cm. by 1 mm. 



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THE TREATMENT OF URETHRAL CARUNCLE 315 

mark the cauterized tissue; these lines are separated by normal 
mucosa. Within a week all evidence of the operation disappears. 
The advantages of this method of removal of urethral caruncles are: 

1. The entire growth can be removed at a single operation. 

2. The operation can be done without pain under local anesthesia. 

3. Bleeding does not obscure the field during the operation nor 
annoy the patient afterward; the operator may be sure, therefore, 
that all the growth has been removed and recurrences thus avoided. 

4. There is a minimum of scar tissue since there is no sloughing as 
the destruction of tissue is absolutely under control. The small 
amount of scar tissue remaining is in longitudinal lines and separated 
by islands of healthy mucosa so that a postoperative prolapse of the 
mucosa due to contraction of the scar does not occur. 

5. Symptoms are relieved almost immediately. 

6. The specimen removed is not destroyed and may be sectioned 
for microscopic study. 

During the past four years 118 patients have been treated by this 
method; so far we have learned of only four recurrences. 

BIBLIOGRAPHY 

1. Ballenger, E. G., and Elder, 0. F.: The treatment of urethral caruncles by fi- 
guration. Jour. Am. Med. Assn., 1917, lxix, 1420. 

2. EnglJsch: Retentionscysten der weiblichen Harnrohre bei Neugeborenen und 
ihre Beziehung zur Entwickelung der Carunkel. Wien 187S. Quoted by Neuberger. 

3. Kretschmer, H. L.: Fulguration for urethral caruncle. Surg. Clin, of Chicago, 
1918, ii, 833. 

4. Murphy, J. B.: Urethral caruncle — ablation. Surg. Clin, of J. B. Murphy, 
1916, v, 45-56; 913-915. 

5. Neuberger, J.: Ueber die sogenannten Carunkeln der weiblichen Harnrohre. 
Berl. klin. Wchnschr., 1894, xxxi, 468-472. 

6. Nicolson: Urethral caruncle simulating cystitis. Urol, and Cutan. Rev., 1916, 
xx, 555. 

7. Smith, A. L.: Notes of cases at the Samaritan Hospital for Women, Montreal. 
Internal Clin., 19 s., 1909, iii, 164-177. 

8. Virchow: Die krankhaften Geschwulste, Berlin, Hirschwald 1867, iii, 464. 
Quoted by Neuberger. 

9- Wiener, S.: High frequency cauterization and treatment of urethral caruncle. 
New York Med. Jour., 1913, xcviii, 1115-1116. 

lO. Young, E. L., Jr.: Urethral caruncle. Boston Med. and Surg. Jour., 1915, 
xlxxii, 822-824. 



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DISEASES AND TREATMENT OF THE PROSTATE 

GLAND* 

E. S. JUDD. 



The prostate gland is a part of the generative system and its func- 
tion is that of secreting a substance which acts as a sustainer and 
carrier medium for the spermatozoa. The gland is developed from 
several series of embryonic buds which form its several lobes. The 
activity of the gland is confined to adult life; during that time it is 
seldom subject to any pathologic processes requiring surgical treat- 
ment. An inflammatory process, frequently associated with a specific 
infection in other parts of the genito-urinary system, may occur and 
at times may progress to the point of suppuration, although this con- 
dition is rare compared with the frequency of infections elsewhere in 
the body. 

Tuberculosis may also involve the prostate during early adult life 
either as a primary focus in the gland or secondary to a lesion in the 
epididymis or kidney. The question of whether tuberculosis of the 
prostate should be treated surgically has been widely discussed, because 
of the fact that when the condition occurs as a secondary process it 
usually subsides after the primary focus has been removed. 

Several years ago Alexander advocated the removal of the inflam- 
matory lesion when it is associated with specific infection, but his 
opinion has not received general approval, largely, I believe, because 
most patients recover from the ordinary, conservative procedure. It 
may, therefore, be said that except in cases of suppurating inflamma- 
tory processes it will seldom be advisable or necessary to operate on 
the prostate during early adult life. 

The prostate gland is of special interest surgically at the period 
in which it is becoming physiologically inactive. At this time the 
pathologic condition which very commonly occurs in the gland, and 
which is so peculiar to it, begins to develop. This so-called 
adenomatous hypertrophy is probably present in almost all men past 

* Presented before the Michigan State Medical Society, Detroit, May, 1919. 
Reprinted from Jour. Mich. State Med. Soc, 1919, xviii, 469. 

316 



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DISEASES AND TREATMENT OF THE PROSTATE GLAND 317 

55, although it produces symptoms only in persons in whom the en- 
largement interferes in some manner with the mechanism of urination. 
Usually the first change that is noticed is urination during the night, 
and this may be the only indication. I am firmly convinced after 
careful questioning and after studying the condition of men who come 
for examination for various complaints at this time of life, that most 
men who reach 55 to 60 have some enlargement of the prostate. 
This is evidenced by frequency of urination or by enlargement or 
change in the prostate which may be discovered on rectal examination. 
Prostatic hypertrophy has often been attributed to some infection 
resulting in urgency, frequency, and difficulty of urination. Usually 
these symptoms first appear at intervals, later they become more fre- 
quent, and finally they are continuous. Complete retention which 
may occur early in the course of the trouble is often associated with 
some other condition such as an infection in the form of a cold in the 
nasopharynx. Ordinarily the first symptoms are not at all serious 
and may cause little if any inconvenience. Before long, however, 
incomplete emptying of the bladder and an increasing amount of 
residual urine becomes evident. This condition, with its resultant 
changes, is the most serious feature to be considered in dealing with 
these cases. Just how these secondary changes are brought about 
has not been definitely shown, although it is well understood that with 
the increase of symptoms and the amount of residual urine the dis- 
turbance in the functioning capacity of the kidneys increases. This 
change in the equilibrium may be so gradual that the patient is scarcely 
aware of his condition while in reality through gradually diminished 
kidney function, he has almost reached the uremic state. The 
decrease in renal function may be most marked in cases in which the 
local bladder symptoms are not pronounced; in dealing with the condi- 
tion this point must be thoroughly understood in order to avoid 
unpleasant surprises. Because of this much stress has been laid on 
the importance of preoperative treatment by those who have had the 
largest experience. Patients with uremia do not withstand operations 
well; the tendency to uremia must be overcome before any surgical 
procedure should be considered. Not all patients reach this state 
before they come for consultation and therefore all patients do not 
require preoperative treatment, but if the amount of residual urine 
is considerable and the kidney function is reduced, preoperative treat- 
ment is certainly most important; it not only changes postoperative 



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318 E. S. JUDD 

convalescence and complications but also very greatly reduces the 
mortality following operation. All credit is due the laboratory worker 
for devising an accurate method of determining the renal function, for 
by these tests we are able to follow cases through the preparatory 
stage and to determine definitely when the function has returned 
sufficiently to make surgical treatment safe. The general physical 
state of the patient is of great importance as other considerations, 
aside from diminished renal function, may contra-indicate any opera- 
tive work. In my opinion, an estimate of the blood urea is necessary; 
if the urea is excessive any operative procedure is contra- indicated even 
if all other findings seem to show that conditions are satisfactory. 

During the preoperative care which consists in carrying the patient 
through the state of reaction following the withdrawal of residual 
urine by a urethral catheter, or by a suprapubic drain, a perfectly 
characteristic reactionary condition occurs. The patient becomes 
weak, is unable to sleep or rest, is very nervous, loses weight, and is 
altogether miserable. The specific gravity of the urine drops; the 
phenolsulphonephthalein output and blood urea are often evidence 
of disturbed renal function. The reaction usually subsides in two 
or three weeks although it may require much more time. At this stage 
of the treatment the patient is in much better condition than he has 
been for years and the obstructing prostate is removed purely for the 
relief of the mechanical disturbance in the urethra and bladder. I 
emphasize these general changes in the patient with adenomatous 
hypertrophy of the prostate since they are characteristic of this type 
of case, probably because the condition produces more mechanical 
disturbance than some of the other pathologic processes which must 
be considered. 

In contrast to the inflammatory prostatic changes occurring in 
younger men, which are not ordinarily considered surgical, is the in- 
flammatory prostatic disease occurring in older men which is more 
often benefited by surgery than by any other form of treatment. 
Possibly the prostatitis of older men is a continuation of an earlier 
process; sometimes the history of the case will bear this out, although 
a distinct group of persons who have definite prostatitis after middle 
life present no history nor evidence of an inflammatory process in 
early life. This condition is sometimes described as a prostatic bar 
or a small hard prostate. In some instances calculi are deposited 
within the gland acini and a calcareous prostatitis is the result. 



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DISEASES AND TREATMENT OF THE PROSTATE GLAND 319 

Frequently a marked cystitis and at times a pyelonephritis, possibly an 
old inflammatory process in the epididymis and testicles, are associated 
with the condition. The bladder is usually inflamed, trabeculated 
and thick-walled, and may contain one or more diverticula. The 
patient complains of considerable pain in the perineum and of symp- 
toms of cystitis. Usually there is not a great amount of residual 
urine. Such patients require preoperative treatment not primarily 
because of the residual urine, but to clear up the infection as much as 
possible. Frequently local treatment with prostatic massage is given, 
but in our experience permanent relief is not often obtained; much 
greater benefit follows suprapubic removal of the inflammatory tissue. 
The transvesical operation is especially indicated in these cases as it is 
difficult to remove the inflammatory scar tissue, and the sphincter 
muscle may be injured if the perineal operation is employed. Chronic 
prostatitis, with or without calculi, does not receive the consideration 
from a surgical standpoint which I believe it deserves. Temporary 
relief in these cases is obtained by conservative methods of treatment, 
but all the symptoms return when the treatment is stopped. In most 
instances complete and permanent relief will be assured by the more 
radical surgical measures. 

Another condition frequently associated with pathologic changes 
in the prostate is diverticulum of the bladder. I am convinced that 
the condition occurs more frequently than we have supposed and that 
we will recognize the condition much more often if we are on the 
lookout for it. Many of the cases of so-called protracted cystitis 
not relieved by prostatectomy are really cases of diverticulum of the 
bladder. In any case in which there is a great deal of infection in the 
bladder and especially if the cystitis is of the foul smelling type we 
may expect to find a diverticulum, and only by the removal of the 
diverticular sac as well as the prostatic obstruction will complete relief 
be afforded. Removal of the obstruction and drainage of the diver- 
ticulum will not suffice. 

The present results of the surgical treatment of malignant disease 
of the prostate are not gratifying. This condition differs entirely 
from other pathologic lesions in the gland especially since it almost 
invariably originates in the small posterior lobe of the gland and its 
extension is upward beneath the bladder and between the seminal 
vesicles before it involves other parts of the prostate or the bladder 
itself. For this reason the disease may become quite extensive before 



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320 E. S. JUDD 

any urinary symptoms are noted. Many cases are on record in which 
a carcinoma of the prostate has been known to exist for a number of 
years without producing symptoms. I have observed several untreated 
patients over a period of more than five years who were in compara- 
tive comfort. 

In view of the fact that cancer of the prostate originates in the 
posterior lobe in close association with the anterior part of the rectum; 
that the disease is an infiltrating process which is not encapsulated 
and a complete removal of all sphincter control of the bladder is 
necessary thoroughly to eradicate the disease; that the cancer in 
itself may exist for some time without producing much if any dis- 
comfort; and that radium applied by the radium needles will probably 
greatly prolong the period so that the patient may live many years in 
comfort, it is probably best to consider cancer of the prostate as not 
satisfactorily amenable to radical surgical procedures. A certain 
number of patients with cancer of the prostate have difficulty with 
urination, and this may be due to the enlargement of the cancer or 
more likely, to an associated adenomatous hypertrophy. In either 
event if there are no other contra-indications it is advisable to remove 
the adenomatous enlargement or enough of it so that urine may be 
expelled easily; the operation should be followed by radium treatment. 
Cancer of the prostate, we believe, should be operated on only when 
it interferes with urination; our results, both with regard to the comfort 
and the convalescence of the patient following radical operation do 
not warrant its employment. Some patients are undoubtedly greatly 
benefited by radium. 

Regarding the technic of the operation for the removal of enlarge- 
ments in the prostate: We are endeavoring to take the operation from 
the realms of the rather blind and rapidly performed operation to one 
performed as much as possible under the guidance of the eye with 
a technic as definite and accurate, as that of any abdominal operation. 
It is difficult in all patients to expose the prostatic region, and es- 
pecially in those who have been operated on before. In the great 
majority of cases the area can be brought into view, however, so that 
the operation may be carried out very accurately. The entire enlarge- 
ment can be enucleated and any tags removed. Bleeding, which is 
one of the most important features in the technic, can usually be 
absolutely controlled in doing the open operation. In many instances 
the bleeding comes from a single vessel and a single ligature will 



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DISEASES AND TREATMENT OF THE PROSTATE GLAND 321 

make the field dry. The old idea that the loss of blood is good for 
such a patient no longer holds. There is less tendency to infection 
in the open operation; the tissues are protected and less traumatized. 
The operation of prostatectomy must be considered a major operation 
and, as in other operations of this degree, the more accurate the technic 
the more satisfactory will be the result. 



'19—21 



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THE OPERATIVE TREATMENT OF VESICOVAGINAL 

FISTULA* 

E. S. JUDD 



Fistulas between the bladder and the vagina are the result of 
difficult parturition, or some operative procedure, most often the 
extirpation of the uterus for cancer. In the early days most of the 
cases of fistula that were under observation were the result of trauma 
at the time of childbirth. It was in the treatment of such cases that 
Sims developed the first accurate operative technic for their repair. 
In later years, however, several factors have arisen to change condi- 
tions materially. In the first place, better obstetric management has 
greatly reduced the number of fistulas which occur as the result of 
difficult labor, but there has been a great general wave for the radical 
extirpation of cancer both by operative procedure and by cautery 
and large doses of radium. While the ultimate results of these opera- 
tions and treatment warrant the procedure they very greatly increase 
the number of cases of vesicovaginal fistula. Sampson, in 1904, 
reported 19 cases following 158 hysterectomies for carcinoma of the 
cervix, while a review of the cases in which we have operated since 
1908 shows that 61 per cent of our cased have resulted from some 
operative procedure for the removal of tumors of the uterus, and 
only 39 per cent followed childbirth. These percentages undoubtedly 
would be d fferent in a strictly obstetric and gynecologic clinic, but 
they indicate the cause of the fistulas which are generally seen. 

The occasional satisfactory result of the treatment of a carcinoma 
of the cervix which is extensive and involves the vaginal mucosa 
undoubtedly warrants the continuance of treatment in such cases. 
The apparent complete disappearance of a large cauliflower cancer 
of the cervix after a few treatments with radium is most striking, 
but these treatments should not be undertaken without considering 
the fact that a fistula from the bladder may result from the use of 

* Presented before the Western Surgical Society, Kansas City, December, 1919. 
Reprinted from Surg. Gynec. and Obst,, 19S0, xxx, 447-553. 

322 



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OPERATIVE TREATMENT OF VESICOVAGINAL FISTULA 323 

radium alone as well as from operation or cautery. If the malignancy 
is eradicated so that the fistula may be repaired satisfactorily the 
operation is certainly justified, but if the patient is left without control 
of the urine and with malignancy persisting in the edges of the fistula 
or evident in other places, the treatment cannot be justified. For 
this reason the extent of involvement must be studied carefully to 
make sure that the patient has some chance of relief before the addi- 
tional risk is taken. Radium has been a great help in the treatment 
of cancer of the cervix and ordinarily it can be used without the dan- 
ger of injury to the bladder, although there are 5 cases in our series 
in which the fistulas followed the use of radium alone. 

The scar resulting from the cautery or radium renders the technic 
of the operation much more difficult than in the cases which follow 
childbirth. The scar from the use of the cautery is thick and firm and 
it is very troublesome to free the tissues so that the flaps may be approxi- 
mated and sutured. The flaps tear readily so that care must be 
taken in forcing the needle through them. The scar resulting from 
the trauma of parturition is much smaller and the tissues are much 
more pliable and easier to suture. 

The apparent ease with which vesicovaginal fistulas may be closed 
is sometimes deceiving and, unless definite principles are followed, 
the results will not be uniformly satisfactory. Too many times, I 
believe, an attempt is made to close the opening before dissecting the 
bladder wall well away from the vaginal wall. In some instances it 
may be possible to close the opening in this manner, but I agree with 
recent writers on the subject who emphasize the fact that the under- 
lying principle of the technic of the operation is the separation of the 
wall of the bladder from the wall of the vagina. The condition which 
keeps the fistula from healing of its own accord is the fact that the 
mucous membrane of the bladder and vaginal wall have healed to- 
gether, thus forming a continuous mucous membrane surface from 
the bladder to the vagina. The first essential in the treatment 
consists in destroying the communication, and the best manner of 
accomplishing this is to dissect the bladder completely away from the 
vagina as is done in the operation for the relief of cystocele. If the 
mucous membrane of the fistulous tract is not freed so that it can be 
turned into the bladder on the one side and into the vagina on the 
other the communication will almost certainly reform. A review of 
our cases shows that often several operations have been necessary 



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324 E. S. JUDD 

before the fistula closed permanently. Sixty-eight per cent of our 
patients had been operated on before coming to the clinic from one 
to seven times. In most instances these operations had apparently 
been done well; in others I believe the operator had been deceived 
into performing an operation by its apparent simplicity. Undoubtedly 
a certain percentage of these patients require more than one operation, 
and I believe we are justified in repeatedly attempting to try to close 
the fistula if the sphincter muscle has not been destroyed. If the 
urethra and the sphincter muscle are destroyed there is nothing to be 
gained in operating to close the fistula as the urine will continue to 
escape. At times the urethra may be destroyed and the sphincter 
be intact ; in these cases the operation should be performed as the 
absence of the urethra will not cause any great inconvenience. In 
other cases the sphincter may be divided or torn by trauma and there 
is every liklihood that the sphincter will functionate if it is repaired; 
therefore operation to close the fistula and repair the sphincter should 
be done. It seems to me that the operability of these cases depends on 
whether or not there is a sphincter muscle. Even though it is severed 
any number of attempts should be made to repair it before the only 
other feasible procedure is advised, that is, some plan of diverting the 
urine to the rectum, thereby leaving it under the control of the rectal 
sphincter; this may be done if the sphincter of the bladdei is completely 
destroyed. Probably Keen's plan is the best one to adopt in these 
unfortunate cases, that is, to make a large communication between the 
vagina and rectum just above the anal sphincter and then close the 
vaginal outlet. In Keen's case the woman defecated and urinated 
for more than thirty-five years and menstruated for eleven years by 
rectum. Peterson collected 41 cases in which this operation was 
performed with comparative success. In one case only the patient 
died of a kidney infection and that was some months after the opera- 
tion; the infection was not believed to be due to the entrance of organ- 
isms from the colon to the bladder. 

The basis of this review is the 78 cases is which operation was done 
in our clinic from January, 1908 to September, 1919.* In 54 of these 
cases it was possible to close the fistula at one operation; in 16 two 
operations were performed and in 1 six operations failed completely 
to close the fistula. The size of the fistulous opening in these cases 

* I am greatly indebted t j Dr. R. G. Andres for his careful study of our case records 
and the resulting data. 



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OPERATIVE TREATMENT OF VESICOVAGINAL FISTULA 325 

varied from the size of a small pin-point to complete eveision and pro- 
plapse of the bladder. Complete prolapse of the bladder into the 
vagina occurred in 2 cases, one following childbirth in which several 
operations had formerly been done, and one following combined 
cautery and radium treatment for cancer of the cervix. In the first 
case the fistula was repaired successfully, but in the second case the 
repair was not complete; the entire anterior part of the rectum had 
been destroyed by the use of the cautery, and it was impossible to 
keep the field of operation clean. 

In 75 cases the fistulous opening was single; in the other 3 cases 
there was more than one opening. The multiple fistulas did not offer 
any more difficulties than the single. A large incision in the vaginal 
wall included.all the openings and converted the operation into a single 
closure after the openings into the bladder had been separately 
closed. 

The bladder sphincter was involved in 10 cases, but it was de- 
stroyed in only 3; it was repaired quite satisfactorily in the 7 cases. 

One of the ureters was involved with the vesical fistula in 6 cases. 
I believe that it is very important to determine the relationship of the 
ureters whenever it is possible. In a few instances the opening of the 
ureter was found close to the edge of the fistula and it was possible to 
turn it into the bladder, or at least avoid injuring it. In several of the 
cases in which the ureter was involved the suprapubic operation was 
performed; the ureter was transplanted if it appeared to be in good 
condition, and the opening of the vesical fistula closed. In one of 
these cases the ureter was thickened and evidently had been completely 
occluded for a long time so that it seemed advisable to ligate it. 

In all cases in which the suprapubic operation was selected it was 
selected for some special reason; it was not employed generally in 
vesicovaginal cases. The patients on whom the suprapubic operation 
was performed have all done well, and their convalescence was more 
favorable than might have been expected. While the suprapubic 
operation offers a good chance for cure, it also offers a greater oppor- 
tunity for infection, and should not, therefore, be chosen unless espe- 
cially indicated. Our suprapubic operations were performed 
extraperitoneally. 

Trendelenburg, is credited with having performed the first supra- 
pubic operation for vesicovaginal fistula in 1890, and, according to 
Ward, there were 27 of these operations reported within the next four- 



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S26 



E. S. JUDD 



teen years. Fewer operations have been reported duiing the past 
fifteen years, probably on account of the added risk of infection. 

Legueu has recently advocated the transperitoneal vesical route for 
vesicovaginal fistula. One of his 1$ patients operated on by this 
method died. He claims for this method wide exposure and every 
security for healing since in making closure the bladder incision is 




Fig. 147. — Dotted line indicating area around fistula to be incised. 

covered by peritoneum. Such suprapubic operations undoubtedly 
should be carried out in some of the very bad cases, especially if the 
ureter and bladder are traumatized. In certain instarces the fistulous 
tract becomes attached to the pubic bone and is thus held in a most 
inaccessible position, making closure difficult by the vaginal route. In 
some of these cases the suprapubic operation can be used to advantage. 
In most instances cases of vesicovaginal fistula can be dealt with 
satisfactorily by making plastic closure of the fistulous openings 



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OPERATIVE TREATMENT OF VESICOVAGINAL FISTULA 



327 



through a vaginal incision. If the opening is small the technic de- 
scribed by C. H. Mayo may be followed, that is, inverting the fistula 
into the bladder. The inverted fistula is held in the bladder by tension 
on the purse string suture which is pulled out through the urethra. 

Crenshaw, of our staff, has closed a number of small vesicovag- 
inal fistulas by the use of the high frequency current. If the fistula 
is small it is well worth while to try this method before attempting an 
operation. 




Fig. 148. — Incision completed and vaginal wall retracted. 



Before any operation is undertaken an effort must be made to get 
the tissue in the best possible condition for healing. This frequently 
requires several week since often the mucous membrane of the vagina 
and of the labia, and even the skin of the thighs are excoriated and 
infected, and contain deposits of salts. A cystoscopic examination 
should always be made in order to determine the position of the ureters, 
the presence or absence of a sphincter muscle, and whether or not the 



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328 



E. S. JUDD 



bladder is completely severed from the urethra. One of the greatest 
difficulties encountered is trauma to the vesical neck. The vaginal 
operation certainly should be chosen in all cases of injury near the 
neck of the bladder, the part difficult to expose by suprapubic incision, 
so that in such injuries this incision would be distinctly contra- 
indicated. If the opening in the bladder is high in the vaginal fornix 
and especially if there is much scar tissue, as there is apt to be following 



urall 




Fig. 149. — Dissection of the wall of the vagina from the wall of the bladder. 

cautery or total hysterectomy, it will be difficult to obtain sufficient 
exposure by vaginal incision and in some instances it may seem best to 
perform the suprapubic operation. The fistula can usually be made 
accessible, however, so that the operation may be done through the 
vagina. Very often the perineum is badly torn, and incision into it 
for exposure is not necessary, but if the incision is necessary it should 
be made unhesitatingly and the openings closed at the completion of 



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OPERATIVE TREATMENT OF VESICOVAGINAL FISTULA 



329 



the operation. One of the chief steps in this procedure is a long 
incision in the vaginal wall down to the bladder. Usually the inci- 
sion is begun immediately below the sphincter muscle and extended to 
and through the fistulous opening, after which the bladder is separated 
from the vagina for a considerable distance (Fig. 147). I have found 
it easier to begin this dissection as near the cervix as possible and to 
bring it forward toward the urethra. Unless this step is thoroughly 




Fig. 150. — Suturing the wall of the bladder. 

carried out the chance for a cure is not good. If the cervix has not 
been removed it should be tracted downward as this helps materially 
in the exposure (Fig. 148). If the cervix has been removed and the 
fistula is high in the vagina it may be best to open the peritoneum 
widely in order freely to mobilize the bladder and bring the fistula into 
view. Several years ago Kelly suggested opening the peritoneum and 
I have followed this method a number of times to great advantage. 



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330 



E. S. JUDD 



It must be remembered that loops of intestine are usually caught in 
this scar and are apt to be injured. This accident happened in one of 
my operations, but I was able to repair the opening in the intestine 
without much trouble. Ordinarily I do not believe that it is necessary 
to open the peritoneum, bul in almost inaccessible cases it is helpful. 
Slight infection may follow, although it was nol a complication in 




Fio. 151. — Suturing the wall of the vagina. 

my cases. In one case in which I did not open the peritoneum the 
patient developed a fecal fistula through the vagina several days 
afterward, and I was obliged to repair it by abdominal procedure. 
A small curved hemostat passed through the urethra and into the 
vagina through the fistula has helped us most to bring the fistulous 
tract downward into the dissection. The dissection of the bladder 
should be carried on until the wall is loose and free and until the edges 
can be easily approximated (Fig. 149). In the cases of extensive 
injury this is sometimes impossible and it then seems best to close the 



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OPERATIVE TREATMENT OF VESICOVAGINAL FISTULA 331 

bladder opening as completely as possible without using tension on the 
sutures; complete closure can be made later. If too much dissection 
and tension is employed the circulation to the flaps will be reduced, 
and sloughing of the tissues will occur. Fortunately many of the 
tissues may be separated without harm. It is better to perform two 
or three operations than to carry the procedure too far at one time. 
The opening in the bladder should be closed with catgut and the 



rrvu-C os a, 




Fig. 152. — Closure of the wall of the vagina. 

edges of the mucous membrane inverted (Fig. 150). The vaginal 
incision should be closed with chromic catgut and all dead space 
between the bladder and vagina obliterated (Figs. 151 and 152). 
In case the sphincter has been repaired or the urethra sutured back to 
the bladder it is best to use fine silk sutures in addition to the catgut, 
being cautious not to penetrate the mucous membrane with the silk. 
A retention catheter is left in the bladder for from eight to ten days, 



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332 E. S. JUDD 

and great care must be taken to make sure that it drains properly. 
Patients should be kept quiet for from twelve days to two weeks. 

There was no mortality in this series of cases, and the ultimate 
results were very satisfactory in a large percentage. We have recently 
received information concerning 56 of the 78 patients. Four state 
that they have derived no benefit from the operation; 6 are consider- 
ably improved, although there is still slight incontinence of urine. 
All the other patients are completely relieved and the bladder func- 
tion is normal. 

In conclusion I wish to emphasize points as follows: 

1. Vesicovaginal fistulas are now more common following opera- 
tions than following childbirth. 

2. All vesicovaginal fistulas should be considered operable as 
long as the sphincter muscle of the bladder is intact or can be repaired. 
If the sphincter has been completely destroyed it will be necessary 
to consider some other procedure. 

3. Suprapubic extraperitoneal operations seem to be indicated if 
the cystoscopic examination reveals injury to a ureter as well as to 
the bladder, or it may be indicated if the fistulous tract is adherent 
to the pubic bone. 

4. The plastic vaginal operation consists in completely separating 
the bladder from the vagina and closing the two separately and oblite- 
rating all dead space. 

5. A large percentage of complete and permanent cures follows 
such operations. 



Table 1. — Type of Urinary Fistulas Operated on from January, 1908 to 

September, 1919 

Cases 82 

Vesicovaginal 67 

Vesico-uretero vaginal 6 

Vesico-uretero-uterine 1 

Vesico-uterovaginal 5 

Vesicourethrovaginal 3 

Age of youngest patient 19 years 

Age of oldest patient 64 years 

Table 2. — Causes of Fistulas Cases 

Childbirth 32 (39 per cent) 

Operation 50 (61 per cent) 



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OPERATIVE TREATMENT OF VESICOVAGINAL FISTULA 333 

Type of Operation 

Hysterectomy 31 (IS in our clinic) 

Percy cautery (no hysterectomy) 4 ( 2 in our clinic) 

Excision of cervical stump 3 • 

Percy cautery and radium for recurring cancer 

(previous hysterectomy) 8(2 in our clinic) 

Amputation of cervix 2 

Lithopaxy through urethra 2 

Puncture drainage of bladder for cystitis 3 

Abscess drained through vagina 2 

50 (17 in our clinic) 

Shortest time between occurrence and repair 3 weeks 

Longest time between occurrence and repair 24 years 

Table 3. — Operations Performed Elsewhere 

Repair attempted before coming to clinic in 44 cases 

13 patients had had 1 operation 

15 patients had had 2 operations 
6 patients had had 3 operations 
4 patients had had 4 operations 

3 patients had had 5 operations 
2 patients had had 6 operations 
1 patient had had 7 operations 

No previous operation for repair of the fistulas 38 case* 

Table 4. — Patients Operated on in the Clinic, 78 
54 patients had 1 operation 

16 patients had 2 operations 

4 patients had 3 operations 

1 patient had 4 operations 

2 patients had 5 operations 
1 patient had operations 

Inoperable recurring carcinoma of the bladder ruled out 

plastic operation in 4 cases 

The fistulas varied from a very small opening to complete 
eversion and prolapse of the bladder. 

Table 5. — Extent of Involvement Cases 

Bladder sphincter 10 

Bladder sphincter completely destroyed 3 

Ureter 6 

Single fistulas 79 

Multiple fistulas 3 

Table 6. — Type of Operation 

(Layer suture 
Dissection of fistulous tract and closure 69 cases 

Inversion of edges by tension through meatus 

Suprapubic operation 5 

Transplantation of the ureter 3 

ligation of ureter 1 



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334 E. S. JUDD 

BIBLIOGRAPHY 

1. Crenshaw, J. L.: Personal communication. 

2. Keen, W. W : A case in which for over thirty-five years a woman defecated and 
urinated and for eleven years menstruated by the rectum. Med. Rec., 1919, xcvi 352. 

3. Kelly, H. A.: The treatment of vesicovaginal and rectovaginal fistula? high up 
in the vagina. Bull. Johns Hopkins Hosp., 1902, xiii, 73-74. 

4. Legueu, F.: De la voie transperiton£o-vesicale pour la cure de certaines fistules 
vesico-vaginales. Bull, et mem. Soc. de chir., 1919, xiv, 170-175. 

5. Mayo, C. H.: Repair of small vesicovaginal fistula. Ann. Surg., 1916, lxiii, 
106-107. 

6. Peterson, R. : Substitution of the anal for the vesical sphincter in certain cases 
of inoperable vesicovaginal fistula;. Surg., Gynec. and Obst., 1917, xxv, 391-402. 

7. Sampson, J. A.: Vesicovaginal fistula; following hyperectomy for carcinoma 
cervicis uteri, with special reference to their origin and closure. Bull, Johns Hopkins 
Hosp., 1904, xv, 285-292. 

8. Sims, J. M.: On the treatment of vesicovaginal fistula. Am. Jour. Med. So., 
1852, xxin, n. s., 59 — 82. 

9. Trendelenburg, F. : Uber Blasenscheiden-fisteloperationen und fiber Beckenhoch- 
lagerung bei Operationen in der Bauchhohle. Samml. klin. Vortr., 1890, No. 355. 

10. Ward, G. G.: The operative treatment of inaccessible vesicovaginal fistula? 
Surg., Gynec. and Obst., 1917, xxv, 126-133. 



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ECTOPIC ADENOMYOMA OF UTERINE TYPE (A RE- 
PORT OF TEN CASES)* 

A. E. MAHLE AND WM. CARPENTER MacCARTY 



It is evident, regardless of the amount of literature which has been 
written on the subject, that the importance of adenomyoma has not 
been recognized either clinically or surgically. 

Adenomyomas of the uterus and tubes and those extending into the 
broad ligament were described before 1894 by Babes, Breus, Diester- 
weg, and others. In 1896 von Recklinghausen's complete work, 
Die Adenomyome und CysUadenomyome der Uterus und Tubenwandung 
appeared. Adenomyomas of the round ligament, ovaiian ligament, 
rectovaginal septum, and ovary 14 were reported in the latter part 
of the nineteenth century. So-called adenomyomas occur also 
in the stomach and intestines, and have been described in the kidney 
and gallbladder. In the latter cases, the glandular elements resemble 
those of the tissue in which they are found. 

Cullen, in 1908, in his book, Adenomyoma of the Uterus, published 
a review of 83 cases of adenomyoma occurring in 1283 cases of fibro- 
myomas of the uterus, about 5.7 per cent of all the cases. In 1919, 
MacCarty and Blackman reported a total of 211 cases of adenomyoma 
in 3398 fibromyomas of the uterus, 6.43 per cent of all the cases. 

In 1916, Cullen published his comprehensive work, The Umbilicus 
and Its Diseases, in which he collected all the cases of adenomyoma of 
the umbilicus reported up to that time, 13 in number. Id his opinion, 
it was doubtful whether 4 of these cases should be in. hided in the 
group. 

The 10 cases herewith reported were extra-uterine and extratubal 
tumors, diagnosed at the time of operation as adenomyomas. These 
growths contained glandular portions resembling typical uterine 
mucosa, surrounded by a fibrous connective tissue, and smooth muscle 
stroma, the latter in varying amounts. The distribution of the tumors 
was as follows: Umbilicus 1, abdominal wall 2, sigmoid 1, groin 2, 
and rectovaginal septum 4. 

* Reprinted from Jour. Lab. and Clin- Med., 1920, v, 218-228. 

335 



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336 A. E. MAHLE AXD WM. CARPENTER MacCARTY 

ADENOMYOMA OF THE UMBILICUS 

Case 1. — This patient, aged 42, had been married for twenty-three years, during 
which time she had been pregnant four times, the last pregnancy occurring thirteen 
years before. She had noticed a growth in the " navel ** four years before, but it had 
disappeared until several months before examination. At this time she noticed a hard, 
bluish tumor, which seemed to be growing larger, "broke open," and discharged a 
bloody serous fluid. The tumor became quite painful at the time of menstruation. 

On examination, the enlargement was found, as described, with bluish areas beneath 
an intact epidermis, and, clinically, it was considered a "suspicious tumor/* Excision 
of the tumor was followed by a Mayo operation for umbilical hernia. The tumor had 
no connection with the peritoneum or any abdominal viscus. (Figs. 154, 160 and 161.) 

Some patients in the cases of adenomyoma of the umbilicus re- 
ported by Cullen gave a history of enlargement of the tumor at the 
time of menstruation, and one patient noticed a bloody, serous dis- 
charge which occurred during catamenia. This author, because of the 
very close resemblance, pathologically, of these tumors to adeno- 
myoma of the uterus, believes them to have originated from misplaced 
uterine mucosa or from remnants of Muller's ducts. Goddard, in 1909, 
expressed the same opinion. While this may be correct, we believe 
that up to the present time no conclusive evidence has been offered, 
and that the real origin of these tumors is not positively known. Of 
the cases which have been reported previously, all have been cured by 
simple excision of the tumor. Our patient, who was operated on quite 
recently, has been relieved of all symptoms, but not sufficient time has 
elapsed to assure a permanent cure. 

ADENOMYOMA OF THE ABDOMINAL WALL 

The two patients with adenomyoma of the abdominal wall had 
been operated on elsewhere for retroversion of the uterus, for which 
one had an internal shortening of the round ligaments, and the other a 
ventral suspension. 

Case S. — This patient, aged SO, complained of a tender lump, of two years' duration, 
in the lower abdominal wall, under a previous laparotomy scar. The lump was painful 
at the time of menstruation. 

On examination a palpable mass, 3 cm. in diameter, was found beneath the lower 
end of a median laparotomy scar; this was hard, nodular, and painful to the touch. 
It was apparently not attached to the uterus, and, clinically, was thought to be a 
fibrous tumor in a previous laparotomy wound. 

At operation, the mass was removed; it extended through the abdominal muscles, 
and was attached to the left tube about 4 cm. from the uterine horn. (Figs. 153, 162, 
163. 164 and 165.) 



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ECTOPIC ADENOMYOMA OF UTERINE TYPE 



337 




Fig. 153 (Case 2, 251296). — Adenomyoma of tube and abdominal wall. The 
thickened portion of tube (adenomyoma, Fig. 262) was adherent to adenomyoma of 
abdominal wall. (Fig. 163.) 




Fig. 154. Fig. 155. 

Fig. 154 (Case 1, 261880). — Adenomyoma of the umbilicus cut in cross sections, 
showing small cystic areas filled with dark brown pigment. 

Fig. 155 (Case 3, 177844).— Adenomyoma of the abdominal wall with white 
fibrous bands of connective tissue extending through substance of tumor with cystic 
areas filled with dark brown pigment. 




"19 — 22 



Fig. 156 (Case 5, 109474). — Adenomyoma of the groin. 



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338 A. E. MAHLE AND WM. CARPENTER MacCARTY 

Case 3. — This patient, aged 46, had had a ventral suspension performed several 
years before and had been pregnant nine times, the last pregnancy occurring ten years 
before. She complained of lumps in the abdominal wall, which she had noticed for 
the last year. These lumps had not grown noticeably larger, but were always painful 
following menstruation. 

On examination, a mass was found in the suprapubic region, apparently in the ab- 
dominal wall, movable with it, and possibly connected with the fundus of the uterus. 
Clinically, it was thought to be a fibrous growth, attached to the abdominal wall on a 
previously ventro-suspended uterus. 

At operation, the fundus of the uterus was found attached to the abdominal wall. 
The tumor, 8 cm. in diameter, was situated to the right of the midline, and extended 
down to the right side of the uterus. It was solid, with glandular, cystic areas filled 
with black pigment. Because of its extension into the retroperitoneal tissue, and ap- 
parent inoperability, only a piece of tissue 6 cm. in diameter was excised for diagnosis. 
Figs. 156 and 166. 

In the cases of adenomyoma of the abdominal wall it was not pos- 
sible to trace a direct continuity of uterine endometrium to the adeno- 
myoma. Cullen, however, has shown that in many adenomyomas 
of the uterus this relationship between the endometrium and the 
adenomyoma could be demonstrated. In Case 2, the adenomyoma 
of the tube was adherent to the abdominal wall, and from the similarity 
of the pathologic picture of the two tumors, one is led to believe that 
the adenomyoma of the abdominal wall arose from that of the tube. 
In Case 3, the anatomic relationship to the uterus was established, but 
their pathologic relationship was not microscopically demonstrated. 
It is therefore impossible to say definitely that the adenomyoma arose 
from the uterine endometrium. 

ADENOMYOMA OF THE SIGMOID 

Case 4. — The adenomyoma of the sigmoid occurred in a patient, aged 31, who had 
been married eleven years and pregnant once. She had had an appendectomy, salpin- 
gectomy, and partial oophorectomy performed elsewhere. At that time she was told 
that she had a tumor of the lower bowel which would become a cancer. She presented 
herself at the clinic because of this tumor. X-ray of the colon, and a proctosigmoido- 
scopic examination proved negative. 

At operation a tumor mass was found encircling the sigmoid, involving a segment 
of the bowel 4 cm. in length. The sigmoid and the bladder were adherent to a mass 
around the uterus. Twelve centimeters of sigmoid were removed as well as "tarry" 
cysts of both ovaries. (Figs. 170 and 171.) 

Since the mass in this case was not removed and its true pathologic 
condition was not known, only the anatomic relation between the 
uterus and the sigmoid was established. Leitch, however, reports a 
similar case of an adenomyoma of the sigmoid, in which this viscus 



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ECTOPIC ADENOMYOMA OF UTERINE TYPE 



339 



was attached to the posterior wall of the uterus. Specimens from the 
uterus and the sigmoid showed the same pathologic picture. The 




Fig. 157. — (Case 8, 29640.) Adenomyoma of the rectovaginal septum with epithelium 
intact over tumor mass. 




Fig. 158.— (Case 6, 281149.) Adenomyoma of the groin. 




Fig. 159. — (Case 10, 277751.) Adenomyoma of the rectovaginal septum with 
small cystic areas filled with dark brown pigment. 

simple facts in these 2 cases lead us to believe that the adenomyoma- 
tous tissue invaded the sigmoid from the adenomyoma of the uterus. 
In neither case was the mucosa of the sigmoid involved, thus indicating 



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340 



A. E. MAHLE AND W.M. CARPEXTER M.tcCARTT 



that these growths infiltrate from the outer bowel wall and grow 
between muscle fibers and into the loose connective tissue of the serosa 
and submucosa. 






i ■ ; * - 











Fig. 160. — (Case 1, 261880.) Adenomyoma of the umbilicus. A group of gland* 
are surrounded by a cellular stroma resembling a typical adenomyoma of the uterus. 




••• ^v^I~r«a :>. 



Fio. 161.— (Case 1, 261880.) Same as Fig. 
ADENOMYOMA OF THE GROIN 



160. 



Cases 5 and 6 were classified as adenomyoma of the groin, although 
in Case 6 the tumor was located in the lower right abdomen beneath 
a scar due to an appendectomy. 

Case 5. — This patient who had been married eight years, but had never been preg- 
nant, had come to the clinic five years before because of sterility. At that time her 
examination was negative, except for several small nodules which were felt behind the 
uterus. She returned four years later, complaining of a large gland in the right in- 
guinal space which she had noticed only a short time, and which at the time of menstrua- 
tion became larger and tender. 



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ECTOPIC ADENOMYOMA OF UTERINE TYPE 



341 



On examination, a tumor mass was found, fairly hard and tender to touch, presum- 
ably a gland, 4 cm. in diameter, in the right inguinal group of lymphatic glands. 

The patient returned one year later; the gland had enlarged, and she complained 
of some pain in the back and lower abdomen. Since nothing further was found on 
examination than had been noted on former visits, it was decided to excise completely 
the tumor in the groin. The tumor was diagnosed pathologically adenomyoma 
(Figs. 156 to 167). 

Case 6. — This patient, aged 50, single, had had an appendiceal abscess drained 
twenty-five years before. She complained of a palpable tumor, a right inguinal hernia, 
and a thickening of the appendiceal scar. Four years before she had noticed in this 
scar two small lumps, slowly increasing in size, which became painful at the time of 
menstruation. 












Fig. 162.— (Case 2, 251296.) Adenomyoma of the tube. 

On examination, some induration of the appendectomy scar was noticed, as well as 
a right inguinal hernia and a large pelvic tumor, presumably a fibromyomatous uterus. 

At operation, the fibromyomatous uterus was removed and the inguinal hernia 
repaired from within. Later, under local anesthesia, the appendectomv scar was dis- 
sected out. The specimen appeared as an indurated mass resembling a keloid, but 
underneath were cystic areas filled with brown fluid. This tissue, which extended down 
to the femoral ring, was diagnosed pathologically adenomyoma. (Fig. 158.) 

Those adenomyomas of the groin, which have been reported in the 
literature, were, in most instances, connected with the round ligament. 4 
.The tumors in our cases showed no relation to this structure, but were 
situated lateral to it and, at operation, no association could be estab- 
lished, either to the round ligament or any structure closely related 
to the uterus. 



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842 



A. E. MAHLE AND WM. CARPENTER MacCARTY 
ADENOMTOMA OF THE RECTOVAGINAL SEPTUM 



Cases 7, 8, 9, and 10 of adenomyomas of the rectovaginal septum 
comprise the entire number observed in the Mayo Clinic during a 
period of ten years. Since so much has been written concerning such 




Fig. 163. — (Case 2, 251296.) Adenomyoma of the abdominal wall, showing gland 

lying in a cellular stroma. 




Fig. 164.— (Case 2, 251296.) Adenomyoma of the abdominal wall, showing areas of 
old hemorrhage around striated muscle fibers. 

tumors, we shall not describe our cases in detail,£but consider them 
in a group. The importance of the condition should, however, be 
emphasized. 



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ECTOPIC ADENOMYOMA OF UTERINE TYPE 



343 



Cases 6 to 10. — The average age of these patients was 37, ranging from 33 to 45. 
Two patients were married, one of them was sterile, the other had been pregnant three 
times. Menstruation in each was regular with no intermenstrual bleeding. Two had 
had previous gynecologic operations elsewhere, one a myomectomy and a ventral sus- 
pension, and one a vaginal hysterectomy for hemorrhage and a cervix suspicious of 
malignancy. 

One patient only came for examination because of symptoms traceable to the tumor, 
which were pain in the rectum at the time of menstruation and difficulty in defecation. 
In all the other cases the adenomyomas of the rectovaginal septum were found in the 
course of routine physical examination; all showed a tumor situated in the rectovaginal 
septum, varying in size from 0.5 cm. to 3 cm. in diameter. In no case was there involve- 
ment of the rectal or vaginal mucosa. Only one had a polypoid tumor formation raising 
the vaginal mucous membrane on the posterior vaginal wall. The diagnosis of aleno- 
myoma was not made clinically in any case. 




Fig. 165. — (Case 2, 251296.) A foreign body giant cell absorbing old hemorrhage, 
surrounded by endothelial cells containing old blood pigment. 

The postoperative results are of interest, in that the patient with definite symptoms 
from the tumor complained, three years later, of a pain in the vagina associated with 
a greenish-yellow discharge. This patient had been treated with radium with question- 
able results. The other patients have no subsequent history of note. (Figs. 157, 
159, 169, 172, 173 and 174. 

Pathologically, extrauterine adenomyomas are identical in appear- 
ance regardless of where they are found. They differ grossly from 
adenomyoma of the uterus, in that the cystic areas are larger and the 
contents darker brown. (Figs. 153 to 159.) Grossly, the tumors 
are solid, fibrous, and a of light gray color. Here and there, white 
bands extend into the tumor substance, while between these bands 
are areas, dark brown to almost black, varying in size from the head 
of a pin to cystic areas 1 cm. or more in diameter. On pressure, a 
dark brown fluid exudes from the larger cystic areas. 



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344 



A. E. MAHLE AND WM. CARPENTER MacCARTY 



Microscopically, the stroma consists of fibrous connective tissue 
and smooth muscle fibers, the latter in varying amounts. Within 




Fig. 166. — (Case 3, 177844.) Adenoniyoma of abdominal wall. 

the stroma are gland spaces lined with cylindrical epithelium. Some 
glands are surrounded by a very cellular stroma, the cells of which are 
regular with round or oval nuclei resting in a very fine reticulum, while 




Fig. 167. — (Case 5, 109474.) Adenomyoma of the groin. Note typical uterine gland 
surrounded by cellular stroma as seen in uterine endometrium. 

other glands are immediately surrounded by smooth muscle or con- 
nective tissue. In some portions of the tumor substance there is 
marked evidence of recent and old hemorrhage. In the latter areas 



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ECTOPIC ADENOMYOMA OF UTERINE TYPE 



345 



are clumps of endothelial cells filled with old blood pigment and in one 
of these areas a typical foreign body giant cell is seen enclosing a mass 




Fia. 168. — (Case 6, 281149.) Adenomyoma of the groin. 




V-* 







- C mm ' '• *'* -> 7 ' t 



JPN^p 



. ... cvC 




Fig. 169. — (Case 7, 144034.) Adenomyoma of the rectovaginal septum, showing 
glands surrounded by smooth muscle. 

of blood pigment. The adenomatous portions of these tumors with 
their cellular stroma are identical with uterine endometrium. (Figs, 
160 to 174.) 

Clinically, these tumors give no consistent group of symptoms on 



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346 



A. E. MAHLE AND WM. CARPENTER MACCARTY 



which an accurate diagnosis can be made. However, their location 
and their slow growth, extending over a period of years, suggest benign 
tumors. Further, the occasional relation to the time of menstruation, 
of pain or swelling of the tumor, or less frequently a bloody discharge, 
should be very suggestive of adenomyoma. 

Surgically, adenomyomas, regardless of their remarkable infiltra- 
tive characteristics, should be distinguished from malginancy. Espe- 
cially is this true of tumors in the pelvis, adherent to the sigmoid or 




Fio. 170. 



Fig. 171. 



Fio. 170. — (Case 4, 250372.) Adenomyoma of the sigmoid. 

Fig. 171. — (Case 4, 250372.) Adenomyoma of the sigmoid, showing cellular stroma 
invading muscle fibers. Note old blood and serum in lumen of the gland. 

the abdominal wall or other structures. Adenomyomas may be 
recognized grossly in most cases by the fibrous stroma which contains 
cystic areas filled with a bloody, dark brown, or serous fluid. 

The pathologist should distinguish adenomyoma from carcinoma 
by the regularity of gland structure with normal differentiated epithe- 
lial cells without mitoses, and, in most tumors, by the characteristic 
stroma surrounding the glands. He should also recognize that they 
are benign tumors, that they grow by invasion, and do not metastasize. 

It is also of interest that in our series of cases the true nature of the 
growth was not suspected before operation. Two were diagnosed 
malignant, one questionably malignant, and the others were left to 
be diagnosed pathologically at the time of operation. 



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ECTOPIC ADENOMYOMA OF UTERINE TYPE 



347 



All cases occurred in patients between the ages of 29 and 50. Preg- 
nancy apparently had no influence, for 6 of the cases occurred in 
nulliparous women. 




Fio. 172.— (Case 10, 277751.) Adeno- 
myoma of the rectovaginal septum. 



Fig. 173.— (Case 9, 101953.) Adeno- 
myoma of the rectovaginal septum. 




Fio. 174. — (Case 8, 29640.) Adenomyoma of the rectovaginal septum, showing a 
small cavity surrounded by a cellular stroma containing small glands. 



Of the 10 patients, 6 gave a history of symptoms directly referable 
to the tumor. One stated that a tumor mass was found during opera- 
tion, elsewhere, for other symptoms of which the patient complained 
at that time. The remaining 3 patients had adenomyomas of the 
rectovaginal septum which were so small that they were giving no 



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348 A. E. MAHLE AND WM. CARPENTER MacCARTY 

trouble. In these cases, the symptoms, when they were noted in 
the history, were enlargement, pain in the rectum or vagina at the time 
of menstruation, or a vaginal discharge. 

Our knowledge of the origin of these tumors at present is only 
theoretical, von Recklinghausen thought they arose from the 
Wolffian body or duct. Ivanoff, and later Aschoff, according to 
Lockyer, suggested their origin from the epithelium of the peritoneum 
of the different regions in which these tumors are found. Cullen 
believes that they develop from remnants of Midler's ducts or mis- 
placed uterine endometrium. No doubt more extensive work on the 
embryology of the genito-urinary tract will solve this interesting 
problem. 

BIBLIOGRAPHY 

1. Aschoff, L. : Cystisches Adenofibrom der Leistengegend. Monatschr. f. Geburtsh. 
u. Gyn&k., 1899, ix, 25-41: Quoted by Lockyer. 

2. Babes, V.: tTber epitheliale Geschwtilste in Uterusmyomen. Allg. Wien. med. 
Ztg., 1882, xxvii, 35-48. 

8. Breus, C. : tTber wahre epithelf iihrende Cystenbildung in Uterusmyomen. Wien, 
1894, 36 pp. 

4. Cullen, T. S. : Adenomyoma of the round ligament. Bull. Johns Hopkins Hosp., 
1896, vii, 112-114. 

5. Cullen, T. S. : Adenomyoma of the uterus. Philadelphia, Saunders, 1908, 270 pp. 

6. Cullen, T. S.: Embryology, anatomy, and diseases of the umbilicus, together 
with diseases of the urachus. Philadelphia, Saunders, 1916, 680 pp. 

7. Diesterweg, A. : Ein Fall von Cystofibroma uteri verum. Ztschr. f. Geburtsh. u. 
Gynak., 1883, ix, 191, 234. 

8. Goddard, S. W. : Two umbilical tumors of probable uterine origin. Surg., Gynec. 
and Obst, 1909, ix, 249-252. 

9. Ivanoff, N. S.: Drusiges cystenhaltiges Uterusfibromyom compliciert durch $ar- 
com und Carcinom. Monatschr. f. Geburtsh. u. Gynak., 1898, vii, 295-300. Quoted 
by Lockyer. 

10. Leitch, A.: Migratory adenomyomata of the uterus. Proc. Roy. Soc. Med., 
vii, Pt ii, Obst. and Gynec. Sec., 1913; (Oct. 9), 393-398. 

11. Lockyer, C: Fibroids and allied tumors. New York, Macmillan, 1918, 603 pp. 

12. MacCarty, W. C. and Blackman, R. H.: The frequency of adenomyoma of 
the uterus. Ann. Surg., 1919, lxix, 135-137. 

13. v. Recklinghausen, F. D.: Die Adenomyome und Cystadenome der Uterus" und 
Tubenwandung; ihre Abkunft von Resten des Wolff' schen Kdrpers. Berlin, Hirsch- 
wald, 1896, 247 pp. Quoted by Lockyer. 

14. Russell, W. W.: Aberrant portions of the Mtillerian duct found in an ovary. 
Bull. Johns Hopkins Hosp.. 1899, x, 8-10. 



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MALIGNANT MYOMAS AND RELATED TUMORS OF 

THE UTERUS 

(Report of Seventy-two Cases Occurring in a Series of 4000 
Operations for Uterine Fibromyomas)* 

NEWTON EVANS 



Malignant tumors of the uterus comprise a numerically important 
portion of the malignant tumors in women. In the registration area 
of the United States in 1916 the malignant tumors of the uterus caused 
23.4 per cent of all deaths from cancer in women 19 . The larger 
number of the uterine cancers are, of course, epithelial cancers. 
Zacherl states that the proportion of non-epithelial malignant tumors 
of the uterus to carcinomas is 1 to 40^ or 50. The records of the Mayo 
Clinic for the period of 1910 to 1918 show 22 borderline and malignant 
non-epithelial tumors of the uterus, while during the same period 
there were 873 cases of carcinoma of the uterus, a proportion of 1 to 40. 

Notwithstanding this numerical disproportion there is in the 
aggregate a large number of malignant non-epithelial tumors encoun- 
tered and reported. These, however, have received much less study 
than carcinomas of the uterus, and their pathology is poorly understood 
as compared with that of many other types of malignancy. 

The literature is somewhat extensive, beginning with the writings 
of Virchow in 1860, and followed by papers by Ritter, 1887, Williams, 
1894, Pick, 1895, Gessner, 1899, Weir, 1901, Jacobi and Wollstein, 
1902, and others, who reviewed the principal features of the subject 
at various periods. I shall not undertake to review this literature, 
since excellent re*sum6s have recently been written by Maroney, Geist, 
Proper and Simpson, and others. Kelly and Cullen in their book 
Myomata of the Uterus (1909) present a very interesting and instruc- 
tive discussion of the subject with a detailed description of a large 
series of cases. 

* Work done as a Volunteer Student in Surgical Pathology,' under the direction 
of Dr. W. C. MacCarty, Mayo Foundation, April 16, 1919, to August 15, 1919. 
Reprinted from Surg., Gynec. and Obst., 1920, xxx, 225-239, 

349 



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350 NEWTON EVANS 

Two questions with regard to the pathology of this group of tumors 
apparently have assumed great importance, namely: What is the 
histogenesis of malignant non-epithelial tumors of the uterus? Do 
they originate in pre-existing fibroids? Most observers have con- 
cluded with regard to the first question that practically all spindle 
cell tumors arising in the musculature of the uterus originate from 
smooth muscle cells and tend to differentiate into that type of cell. 
The most potent factors in helping to arrive at this conclusion have 
been the modern methods of studying and of differentiating the tissue 
cell types and, particularly, the application of the differential tissue 
stains of Mallory. The second question seems also to have been 
satisfactorily settled by the work of various observers who have 
demonstrated the existence of malignant myomas and cellular myomas 
within the structure of fibromyomas, other portions of which were of 
the ordinary benign tissue type. Williams, in 1894, gave this point 
careful study. The exhaustive work of Kelly and Cullen on their 
rather large series of cases also makes it plain that these tumors 
frequently originate within the structure of fibroids. The present 
observations lead to the conclusion that this insular transformation 
of otherwise benign fibroids is not usual, for it was not definitely 
evident in any of the large series of cases studied. It seems, therefore, 
that the tumor originates in the uterine musculature, and the structure 
remains unchanged, or that there is a gradual diffuse transformation 
in structure which leads to the formation found at the time of removal. 
This question in reality, however, is of academic interest only. The 
really important point is that these tumors appear as tumors, or within 
tumors which, clinically, and sometimes at operation, cannot be 
distinguished from ordinary fibromyomas except in the very advanced 
stages of growth, when the extensive local infiltration and fixation 
of the tumor makes it suspicious, or recognizable as definitely malig- 
nant. 

From a review of the literature in this field it is evident that there 
is a serious lack of understanding and agreement as to the histologic 
criteria which should govern the diagnosis of malignancy in this class 
of uterine tumors. 

Kelly and Cullen found 17 cases among 1400 of uterine fibromy- 
omas which they were willing definitely to denominate "sarcoma"; 
but in the same series there were 17 other tumors which they looked 
on as suggestive or suspicious of being sarcomatous. 



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MALIGNANT MYOMA8 



351 



Miller refers to the cases of Warnekross, who reported the surgical 
treatment of 7 cases of malignant myoma. Photographs of the tissues 
of these tumors were submitted to Aschoff who gave it as his unquali- 
fied opinion that in only 2 cases of the 7 could the tumors be classified 
as malignant. 



< *■•'■ 



' *•■ 



&&: f j*- 






■ 







Fio. 175. 



Fig. 176. 



^* V'v 





Fig. 177. Fig. 178. 

Figs. 175, 176, 177 and 178. Case 3 (125614). (Mitoses 7,600 in 1 c. mm.) 
Drawings of very large and atypical mitotic figures. Fig. 175 shows a very unusual 
form with four symmetrical rosettes. 

In some of the numerous collected series of cases of uterine fibro- 
myomas the relative proportion which shows malignant change is 
given as low as 0.4 per cent; in others it is as high as 10 per cent. 

Maroney states that the diagnosis "must be a matter of individual 
interpretation in suspicious cases." 



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352 



NEWTON EVANS 



In view of this evident lack of knowledge and lack of acceptance 
of uniform standards of malignancy as well as degrees of malignancy 
in this class of tumors, the principal purpose of this study is to make 







•*• - . V* 






?-:'-v^ 



Figs. 179 (above) and 180. Case 29 (229935). (No mitoses.) Photomicrograph 
high and low power, showing structure of a giant-cell tumor, with one giant cell of 
immense size. Note the size of the immense irregular nucleus with some of the 
surrounding nuclei of tumor cells of ordinary size, and the relatively large amount of 
fibrous stroma. Tumors of this type did not recur after removal (x 100 and x 500 . 



such comparisons of the histologic findings and the clinical histories 
of the material available as will serve to contribute something to the 
establishment of microscopic criteria. 



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MALIGNANT MYOMAS 353 

A composite picture of these characteristics, as presented in the 
writings of several authorities, includes the following points: 

1. Increase in size of tumor cells, as compared with normal muscle 
or benign muscle tumor cells. 

2. Shorter and plumper cells with nuclei more nearly oval than 
normal muscle or benign muscle tumor cells, rounded, and "vesicular" 
nuclei. 

3. Inequality in size and irregularity in shape and arrangement 
of the cells. 

4. Lack of "differentiation" of cells. 

5. Unequal staining of nuclei, and deeply staining nuclei. 

- a . • 




'?V 




Figs. 181 (at left) and 182. — Case 33 (248318). (No mitoses). Giant-cell tumor, 
with very large nuclei arranged peripherally in the giant cells. Much fibrous stroma. 
Large nuclei contain vacuoles (X 100 and X 500). 

6. Presence of immense cells (protoplasmic placques) with hyper- 
chromatic, single, or multiple nuclei (giant cells). 

7. Presence of mitotic figures, typical and atypical. 

8. Decrease or absence of stroma fibers between the cells. 

9. Thinness or absence of vessel walls. 

Kelly and Cullen in the descriptions of their 17 positive cases of 
malignant tumors appear, from a histologic standpoint, to place 
definite dependence on inequality in size and increase in the size of 
the tumor cells. And it is evident that they do not look on the presence 
of mitotic figures or of numerous mitoses as essential to the diagnosis 
of malignancy in these tumors. In 6 of the cases "nuclear figures ' 
are noted, in 9 no mention is made of their presence, and in 2 it is 
stated specifically that they were not seen. 

•19— 23 



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354 



NEWTON EVANS 



Ewing, in discussing the relative malignancy of the different 
malignant myomas, says that the round-cell and the giant-cell struc- 
tures are the most malignant. 




Fig. 183. — Case 2 (77121). (Mitoses 2,400 in 1 cmm.) Cells of immense 
size in a very malignant tumor. Very large dense nucleoli and nuclear vacuoles 
(X 500). 




Fig. 184.— Case 7 (64888). (Mitoses 2,560 in 1 cmm.) Foreign body giant cells 
in a tumor with much fibrous stroma in its structure, but a highly malignant 
tumor (x 240). 

Proper and Simpson, of the New York State Cancer Laboratory, 
in their recent article, Malignant Leiomyomata, . present an extremely 
valuable study of the microscopic characteristics of these tumors, 
since it is based on the correlation of the postoperative course of the 



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MALIGNANT MYOMAS 355 

patients with the microscopic structure of the tumors. They divide 
the tumors into three types varying in the degrees of malignancy 
which possibly represent stages of malignancy. With reference to 
their structure they state that "histologically the tumors may vary 
from those made up of cells of uniform size resembling those which 
make up leiomyomata, but being somewhat shorter and plumper, 
with here and there a mitotic figure, up to tumors comprised of cells 
which are extremely irregular in size and shape, some being masses 
of protoplasm with giant or multiple nuclei, and showing all varieties 
of atypical mitotic figures." This statement seems to mean that 
the presence of the large irregular nuclei and giant cells is in direct 
proportion to the degree of malignancy and is an important accompani- 
ment of the malignant process. This is in apparent accord with 
E wing's statement. Proper and Simpson also make the very impor- 
tant observation that in doubtful cases they depend on the absence 
of mitotic figures as the criterion of a benign tumor. Mallory believes 
that the presence of mitotic figures in these myomas is a definite 
indication that they are capable of infiltration and are, therefore, 
malignant. Lockyer, in his interesting volume on fibroids, recently 
published, says that malignant myomas are often difficult to distinguish 
and emphasizes the tendency to infiltrate and the presence of mitotic 
figures as a distinguishing characteristic. 

The literature contains frequent accounts of metastasis by way 
of the blood stream of myomas which are said to have the structure 
of benign or ordinary fibro myomas. Lockyer refers to cases of this 
kind. Ewing states that so far as he has been able to learn no case 
has been fully studied in which definite variations from the usual 
structure were wanting, although in several instances these variations 
were not very pronounced. Strong is quoted by Maroney as making 
the very radical statement relative to the existence of microscopic 
criteria for malignancy in these tumors, that the "only criterion is 
infiltration and destructive growth. Mere richness in cells, mitoses, 
and even irregularities in size of cell do not constitute sarcoma." 
Strong further states: "There never can be any absolute criterion 
for their malignancy and their interpretation will always.be affected 
by the personal equation of the individual observer." Ewing, sharing 
the uncertainty of practically all observers relative to the microscopic 
diagnosis, says: "Sarcomatous tendencies and precancerous changes 
do not constitute real sarcoma or cancer." It is thus evident that 



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356 NEWTON EVANS 

many "very cellular" tumors or myomas exist which give difficulty 
in classification as far as their real malignancy is concerned and which 
are sometimes classified by the pathologist as malignant, and some- 
times as benign or doubtful. 

Mitotic figures. — From the foregoing statements and other 
observations it may be assumed that, in a general way, the presence 
in the tumor tissue of evidences of indirect cell division is looked on 
as a characteristic of the malignant growths of the types under con- 
sideration. So far as I can learn, however, no attention has been 
given to a determination, in a given case, of the actual or relative 
numbers of mitotic figures as related to the degree of malignancy 
of the tumor, or whether or not any such relation existsi The facts 
presented in the present series of cases show that such relationship 
undoubtedly does exist. 

1 





*. .» 












•J . '. 




. w 




t®. 






T :Vc 








X J 






. *?'* 


J- 




,i ^ 



Fig. 185. — Drawing of nuclei of tumor cells showing changes evidently those of 
direct nuclear diviaion-amitosis. Series showing progressive changes in long, oval 
nuclei of ordinary size. 

The series comprises 72 cases diagnosed as "sarcomatous," 
"cellular," or "very cellular" fibromyomatous tumors in the Labora- 
tory of Surgical Pathology of the Mayo Clinic in the years from 1906 
to 1918 inclusive. All tumors of this kind observed in about 4000 
operations for the cure of uterine fibromyomas are included. 

Table 1 serves to show the very definite relationship between the 
more evident characteristics of the cellular structure of the tumors, 
particularly the presence and relative proportions of the mitotic 
figures, and the clinical outcome of the disease. In each case evidences 
of indirect cell division were searched for and careful estimates were 
made of the actual number of these figures in a given area of the tumor 
tissue; the numerical values were expressed as the number of mitotic 
figures seen in 100 microscopic fields of a Ji2 oil immersion lens. 
These values are also translated in an adjoining column into the 



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MALIGNANT MYOMAS 



357 







number of dividing cells in a cubic millimeter of the tissue, taking 
into consideration in this estimation the thickness of the tissue section. 

The tumors readily divide themselves into three definitely delimited 
groups, on the basis of the number of mitotic figures present. In 
the first IS cases the tumors show from 2200 to 12,000 mitotic figures 
for each cubic millimeter. Cases _^ 

15 to 25 form a group having from 
200 to 800 in a cubic millimeter. 
In the remainder of the cases the 
tumors either contained no figures 
on examination or only a very 
few, one or two being found after 
long searching. One of the most 
noticeable features of the tabula- 
tion is the definite numerical separa- 
tion between the first and the 
second groups, no tumors being 
found which showed a numerical 
value between 800 and 2000. It 
would not be justifiable to con- 
clude that in a larger series of 
tumors, or in another similar series, 
values within this hiatus might 
not be found, yet the numerical 
distinction is so clear-cut that it 
cannot escape notice. 

The real importance of such dis- 
tinctions, however, becomes evident 
when the after-course of these cases 
is considered. Of the 13 patients 
in the first group, 11 had recurrences within periods of from one month 
to eighteen months. Only 2 patients are known to be living; they 
give no indication of a return of the malignant tumor, seven months 
and four months respectively, since operation, periods too short to 
preclude the possibility of later recurrence. However, since the 
recurrences were rapid in the other cases one is justified in hopeful 
prognoses in these 2 cases. 

In definite contrast to the cases in the first group, in the 11 cases 
in the second group, having mitotic figures in the proportion of 200 




I 









Fig. 186. — Drawing, o. Result of mul- 
tiple change of a long nucleus, b. Forms 
seen in giant cells of tumors having no 
mitotic figures. 



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358 NEWTON EVANS 

to 800 to each cubic millimeter, there has been no mortality; at least 
in the cases about which we have been able to obtain a recent report, 
9 of the 11, and there are good reasons for believing that the same 
is true in the other 2 cases. 

In the remaining group of 48 cases, in which no mitotic figures are 
seen, or only a very few, there is no mortality from recurrence, at least 
in a large majority concerning which it has been possible to obtain 
recent reports. 

This striking evidence of the importance of numerous mitotic 
figures as an indication of definite malignancy makes it desirable to 
study the reports of similar series of cases from this viewpoint. The 
very complete description of the histology and the clinical features of 
Kelly and Cullen's 17 cases makes an interesting comparison possible. 
Eleven of their 17 patients survived the operation and so are available 
for comparison on the basis of after-history. Only 4 of the 11 died 
of recurrence. In each of these 4, mitotic figures are mentioned as 
being present, in one "many" were seen, and in one other as many as 
"six in a field." Of the remaining 7 patients without recurrence, only 
one tumor is mentioned as showing mitotic figures, and in this there 
was said to be "one here and there." One might be justified from a 
study of these descriptions in the opinion that the four fatal recurring 
tumors belonged in the same group with those of this series having 
many mitotic figures, and that the one tumor which had mitotic figures 
"here and there" belonged in the next group having fewer mitoses and 
clinically showing no recurrences. It might be questioned whether 
Kelly and Cullen are entirely right in classifying in their group of 17 
definitely malignant "myosarcomas" the 9 cases which are not 
mentioned as showing mitoses, and 2 which are described specifically 
as not showing such figures. In none of these patients having tumors 
with no mitoses recorded, who survived operation, was there any 
recurrence. 

A personal communication from Dr. Simpson relative to the series 
of 22 cases of this type of tumor recently reported by Proper and 
Simpson indicates that the findings in their specimens, with reference 
to the relative number of mitotic figures in sections of the tumors of 
different histologic types, are substantially in harmony with my series. 

While we are considering the question of mitosis it would be well 
to mention the frequent occurrence, in the tumors composed of a mass 
of very large sized tumor cells, of numerous mitotic figures of unusual 



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MALIGNANT MYOMAS 359 

form and gigantic size. The drawings in Figure 175 show several 
examples, including the unusual figure of a double division resulting 
in the formation of four newly formed symmetrical rosettes. These 
large and so-called atypical mitotic figures are unquestionably always 
a sign of high grade malignancy. 

Giant cells and hyperchromaiic nuclei. — Another histologic feature 
which demands consideration in a study of these tumors is the presence 
in a certain proportion of cells with large, irregular, hyperchromatic, 
and usually multiple nuclei. Some of these are so immense as almost 
to exceed belief (Figs. 176, 177 and 178). The importance of these 
changes in the diagnosis of malignancy or degree of malignancy, 
judging from the statements in the literature of the subject, is usually 
considered to be very great. A study of Table 1 will give a basis 
for rather definite conclusions in regard to this point. 

It is true that in the first group of 13 cases, including all those 
of the series in which there was postoperative recurrence, giant cells 
were present in varying degree, but in a considerable proportion of 
them in comparatively small numbers. Most of the tumors in the 
next group of the series (Cases 14 to 24), none of which recurred, 
that were characterized by a relatively small number of mitotic figures, 
had no giant cells, and only a few had any giant cells. The phenome- 
non of greatest interest, however, is that in many of the tumors of 
the third group (Cases 25 to 72) giant cells were numerous and in 
a few tumors they were piesent in such numbers, and of such size 
and complexity, as to attract attention. It should be remembered 
that in this group there were no recurrences and histologically the 
tumors were characterized by the absence of mitotic figures or by the 
presence of only a very few at the most. A review of the literature, 
indicates that such tumors have usually been looked on as malignant. 
The facts evident in this series compel the conclusion that there is 
nothing to indicate that the presence of the giant cells alone is an 
indication of a high degree of malignancy or indeed of malignancy at 
all. In the tumors showing the greatest tendency to giant-cell forma- 
tion, but without mitotic figures, it is invariably found that the cells 
are not closely packed but are separated by large amounts of fibrous 
stroma with a tendency to hyalinization. Kelly and Cullen believe 
that the frequent association of this type of cell and stroma indicates 
malignancy and that the presence of the hyalinization is an important 
factor in its pathogenesis. It may be concluded that these cellular 



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360 NEWTON EVANS 

changes are a phenomenon of degeneration coincident with fibrosis 
and hyalinization rather than a manifestation of the exaggerated pro- 
ductive and reactive phenomena w^iich characterize true malignant 
tumors. The origin of the cells which take on this unusual type of 
change is somewhat uncertain, but from the cellular relations it seems 
that many of these very large mononucleated and multinucleated 
cells are modified muscle cells while others, from their position in rela- 
tion to minute vascular channels, appear to originate from endothelial 
cells. 






■ 



^ 



V 

* 



\ * 



*n 



'A 



+w A 



Fig. 187. — Case 61 (248302). (No mitoses.) Photomicrograph showing numerous 
long oval nuclei in direct division (X 1000). 

The morphology of these giant cells is distinctly different from that 
of the so-called foreign body giant cells which are found in many 
tumors, in the lesions of the infectious granulomas, and in the vicinity 
of various foreign bodies in the tissues. Those appearing in the tumors 
in our series should be classed as true tumor giant cells. In a few of 
the tumors studied, however, there is a tendency to the formation of 
the foreign body giant cells. This tendency is marked in only one of 
the tumors (Case 7, Fig. 179). In these figures numbers of giant cells 
of this type are scattered throughout various portions. They are 
characterized by a compact densely acidophilic staining cytoplasm 
with numerous small oval or round nuclei centrally located. These 
cells probably have their origin in modified connective tissue stroma 



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MALIGNANT MYOMAS 361 

cells or in some type of wandering cell. In contrast with these cells 
are the characteristic tumor giant cells which have irregularly shaped, 
lightly staining, indistinct bodies with very large, unequally sized, 
irregularly shaped, deeply staining nuclei, usually arranged in a ring 
at the periphery of the cell body. Many of these nuclei have very 
large densely staining chromatin granules, and often the chromatin is 
disposed in threads (Fig. 176). In many of the sections of the very 
malignant tumors many very large cells are found undergoing un- 
usual forms of mitosis. But typical multinucleated giant cells with 
nuclei in the stages of mitosis have not been found. This leads to the 
conclusion that the true tumor multinucleated giant cell forms by the 
direct, or amitotic, division of the nucleus. Such dividing nuclei are 
in fact frequently seen. 

Direct cell division of tumor cells. — Throughout the tissue of a 
large proportion of these uterine tumors are seen nuclear forms, 
the morphology of which can be interpreted only as that of cell division 
by the direct or amitotic method. This is particularly true of those 
tumors which do not belong to the more malignant type, containing 
no mitotic figures, and the growth of which cannot be accounted for 
by mitotic cell division. The drawings and the photographs of nuclei 
thus dividing will give a general impression of the phenomena as seen 
in the sections. There are two distinct forms of such nuclear division. 
One of these is seen in the large nuclei of the large hyperchromatic 
giant cells described in the preceding paragraph. These nuclei may 
divide equally, but more often they divide unequally by a process of 
lengthening and constriction at the middle; the two portions are 
pulled apart, a large strand of nuclear material connecting them, thus 
assuming a distinct dumb-bell shape (Fig. 180). The other form of 
direct nuclear division is seen in the tumor cells of ordinary size, of 
long or short oval shape, or with rounded nuclei. The cleavage is 
usually preceded by a distinct indentation on one side of the nucleus 
before it is separated into two equal parts. The line of cleavage is in 
a distinctly oblique direction, the degrees of obliquity being greater 
in the shorter and plumper nuclei (Fig. 181). Ocassionally nuclei 
of great length will be seen, evidently dividing almost simultaneously 
by a multiple cleavage so that a chain of attached oval nuclei results 
(Fig. 180). 

The conclusion is apparently justified that the direct cellular 
division observed accounts for the tumor growth in the growing 



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362 



NEWTON EVANS 



tumors which show no signs of growth by mitosis. The subject of 
amitotic cell division is discussed at some length by Wilson in his 
book on the cell. He emphasizes three points of special interest in 
this connection: 

1. Cells undergoing amitotic division have a tendency to become 
larger in size than other cells of the same tissue type. 

2. The cells have a tendency to nuclear division without division 
of the cytoplasm, thus producing multinucleated giant cells. Both 
of these tendencies are very definitely illustrated in the large nuclei 




LwUVm 

Fig. 188. — Case 8 (38352). (Mitoses 4,000 in 1 c.mm.) Marked degree of polarity 
and alignment of the most malignant tumor as compared with the irregular arrange- 
ment of the cells in the less malignant tumor. 

of the tumor giant cells which so frequently characterize these tumors 
and especially those not showing definitely malignant tendencies. 

3. Direct cell division is an indication of degeneracy of the cells 
involved. 

On this last point Wilson quotes von Rath: " When once a cell has 
undergone amitotic division it has received its death warrant; it may 
indeed continue for a time to divide by amitosis, but invariably 
perishes in the end." Wilson states, however, that this is probably an 
extreme view as there are definite examples to the contrary in lower 
forms of life. It may be assumed, therefore, that the direct nuclear 
division which was so frequently seen in the tumors of this series 
undergoing fibrosis and hyalinization as well as the marked tendency 



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MALIGNANT MYOMAS 



363 



to giant-cell formation under the same conditions is a manifestation 
of biologically regressive cellular changes. 

Kimura has recently reported an interesting and important piece 
of work which throws additional light on the problem of the relation 
of mitotic figures (or evidence of frequent indirect cell division) to 
malignancy. The purpose of his experiments is to show the influence 
of the x-ray on the growth and invasive power of malignant tumor 
tissue, using susceptible animals (mice) and artificial tissue cultures 
in parallel series. An appropriate dosage of x-ray rendered the cancer 




Fio. 189.— Case 27 (215251). (No mitoses.) See Figure 188. 

tissue incapable of invading the susceptible animals but the artificial 
cultures of the irradiated cancer tissue grew just as freely as the control 
tissue cultures. The remarkable fact was noticed that the tissue 
exposed to the x-ray grew in artificial culture without any mitotic 
figures while the control tissue grew with large numbers of mitotic 
figures. The type of cell division concerned in the growth of the 
tissue which had lost its invasive power in animals must have been 
the direct or amitotic type. It seems that the process of mitotic cell 
division had some relation to the malignancy of the tumors and that 
with the loss of their mitotic figures they lost their invasive powers. 
These interesting results are in harmony with the facts observed in 
the group of malignant uterine tumors in this series since only those 
tumors which contained large numbers of mitotic figures were able so 
successfully to invade the tissue as to recur after removal. 



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364 NEWTON EVANS 

Tumor cell differentiation. — While it is true that in many of the 
more malignant of these tumors there is a decided decrease in those 
characteristics which are considered as signs of differentiation, in 
practically all a greater or lesser degree of spindle shape, polarity, 
and alignment of the tumor cells are recognizable. In some of the 
most malignant this is very pronounced, much more so than in many 
of the cellular tumors which evidently have little if any real malig- 




Fig. 190. — Case 43 (76296). (Very few mitoses.) Gross appearance of section 
through a fixed specimen of uterus containing multiple fibromyomas. One of the 
tumors, a, is very cellular. Its yellow color is indicated by the darker shade in the 
photograph. It contains an area of hemorrhage. 

nancy. This may be easily seen by comparing the appearance of the 
sections in Figure 182. Therefore, it is evident that the presence or 
absence of these characteristics is not an essential criterion. 

The one dependable microscopic feature so far considered is 
clearly that of abundant mitotic figures in the extremely malignant 
cases. The question of the existence of other constant criteria should 
be considered. It seems to me that the most important microscopic 
features aside from the frequency of mitoses are: 



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MALIGNANT MYOMAS 365 

1. The large size of the great mass of the tumor cells in a given 
case, and a marked inequality in their size. In those very malignant 
tumors which are characterized by this type of cellular structure 
many abnormally large mitotic figures are apparently invariably 
found (Fig. 175), and such figures otherwise unusual in their 
morphology. 

2. The relative decrease in the amount of fibrous stroma. 

3. The growth among the tumor cells of blood vessels with very 
thin walls or with walls entirely wanting. 

4. The relative increase in the size of the nucleus of the tumor 
cells as compared with the mass of the cytoplasm of the cell body. 




Fig. 191.— Case 11 (213999). (Mitoses 12,000 in 1 c.rnm.^ Natural size of a 
section through the fixed specimen. The smooth appearance of the cut suiface is 
evident in contrast to the fibrous appearance of the ordinary fibroid. 

While all these changes are important, careful study of the material 
shows that none is constant, that is, invariably present in the very 
malignant tumors, and always absent in those not malignant. Not- 
withstanding this fact, it is well to note that the tumors composed 
of a mass of closely packed cells of very large size are invariably 
extremely malignant, although it is not true that all the malignant 
tumors have this particular morphology. 

It would be rash to maintain that other constant, easily recogniz- 
able microscopic criteria of this particular type of malignancy do 
not exist; but up to the present time I have not been able to recognize 
any single criterion which is constant aside from the peculiarities in 
mitoses, although the presence of several of the prominent characteris- 



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366 NEWTON EVANS 

tics when occurring in combination may possibly be sufficient to insure 
the accuracy of the diagnosis of malignancy without giving any atten- 
tion to the question of mitotic figures. 

Frequency of occurrence. — Reference to the literature indicates 
that frequently efforts have been made to estimate the indicence of 
the malignant non-epithelial tumors of the uterus with the total 
number of cases of uterine fibroids. Table 2 gives an idea of some of 
the results. The wide variation of these estimates is no doubt largely 
due to the absence of uniform standards rather than to actual variation 
in the incidence of the malignant tumors. 

The 72 patients in the present series, in which the cellular and 
definitely malignant tumors are included, were examined in the Mayo 
Clinic during the years 1906 to 1918 and three months of the year 1919, 
during which time operation was done in approximately 4000 cases 
of uterine fibroids. However, in order to obtain relative figures 
which will have much value as an indication of the real incidence of 
these tumors of varying degrees of malignancy, it will be necessary 
to make the comparison from material collected over somewhat 
shorter periods, since only during the past few years has sufficiently 
painstaking investigation been made of all the fibroids which are 
removed at operation to insure the recognition of practically all the 
unusual myomas, particularly those of the lesser degrees of malig- 
nancy. Among the 968 cases of operation for removal of fibromyomas 
during the two years 1917 and 1918 were 6 cases of the most malignant 
type, those tumors containing from 2200 to 12,000 mitotic figures to 
the cubic millimeter. When the tumors having from 200 to 800 
mitotic figures to the cubic millimeter are included there are 12 in all; 
and including all these with the remainder of the series, that is, those 
having the cellular structure but lacking the frequent mitoses, gives 
38 in all. The percentage for the first group was 0.62, for the first 
and second groups together 1.25, for the three groups 4.00 

During the period from 1910 to 1918 inclusive the total number of 
fibroid operations was 3297; only 13 cases (0.39 per cent) belonged 
to the very malignant group; adding the 9 cases of the second group, 
there are 22 cases (0.67 per cent). The figures for the third group of 
this longer period are too inexact to be included. When the figures 
for the two year period and those for the nine year period are compared 
the percentages for the shorter period are found to be definitely larger; 



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MALIGNANT MYOMAS 367 

t 

and it is probably safe to conclude that these larger percentages more 
nearly represent true conditions. 

A comparison of the percentages for the two year period with the 
figures taken from those of other observers, as shown in Table 2, leads 
one to believe that in a rough way those series which give percentages 
less than 1 per cent are made up of only the most malignant tumors, 
those in Group 1. This would include such groups of cases as Broun's 
1500 cases at the Woman's Hospital, New York, and the 337 cases 
of Noble. Those series giving percentages between 1 and 2 are prob- 
ably made up largely of cases that would be included in our Groups 
1 and 2. The higher figures are no doubt in series which include not 
only the more malignant types but also practically all the cellular 
tumors, the majority of which manifestly show little malignancy 
clinically and, as we have shown, contain few or no mitotic figures. 

Degrees of malignancy and relation of the different types of 
tumors. — Three questions remain to be considered. (1) The degree 
of malignancy of the tumors which are classified outside the group 
of manifestly malignant tumors, but including tumors none of which 
recurred after removal (Groups 2 and 3). (2) The question of the 
biologic relationship between these less malignant tumors and the 
most malignant ones. Are they a fixed type of tumor, or are they 
simply in a stage of metamorphosis, representing a transition stage 
between the ordinary fibroid with its mature, fully differentiated 
type of cell and the real cancer? (3) Is it not possible that these very 
cellular myomas with short spindle cells and short plump nuclei 
and an occasional mitotic figure are simply ordinary fibromyomas in 
an actively growing phase, and at a later period may they not cease 
their active growth and become ordinary fibroids with the structure 
that the majority of fibroids possess? With regard to the last of 
these questions it seems possible that there may be a stage of growth 
in which the balance may turn in either direction; on the one hand, 
back to the fully differentiated type and, on the other, to a still more 
active tumor growth in which the cells vary more widely from the 
adult type and in which the increased rate of growth and increased 
power to invade tissue is indicated by an increased number of mitotic 
figures. 

With regard to the first two of these questions the positive opinion 
seems justifiable, although not proved, that the actively growing 
tumors which contain an appreciable number of mitotic figures are 



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368 NEWTON EVANS 

• 

in a stage of transition toward actual malignancy and, if undisturbed, 
will become malignant. 

A tentative classification of the tumors of this series, exclusive 
of those in the first group, those definitely malignant, is as follows: 
Group 2 includes those with a mitotic figure content of from 200 to 
800 to the cubic millimeter and should be looked on as in a transition 
stage, borderline tumors between the definite malignant group and 
the remaining group of cellular tumors. The cases in Group 3 are 
premalignant and as such presumably have malignant tendencies. 

Gross characteristics. — These uterine tumors appearing in the 
locations of, and in form and general appearance resembling fibro- 
myomas, have a color and consistency which as a rule are characteristic; 
and it should be remembered that they occur frequently in the uterine 
ligaments and other locations where fibromyomas are found. The 
color is difficult to describe but is remembered when once seen and 
recognized. It may be said to be a shade including pink, yellow, and 
gray. Fixed gross specimens have a yellowish tinge, which distin- 
guishes them from the ordinary fibroid. The tissue is much softer 
and has a smooth homogeneous cut surface as compared with the firm 
fibrous surface of the usual fibroid, and it is decidedly more friable. In 
the definitely malignant forms the tumor mass is still more friable 
and varies in color, due to hemorrhage and degenerative and necrotic 
changes. In most of the tumors of the definitely malignant type the 
infiltration and destruction of the uterine and other pelvic structures 
involved is evident, but the less malignant forms are usually as defi- 
nitely delimited from the surrounding myometrium as is the ordinary 
fibroid. 

Metastasis. — Definite indications of metastasis to distant organs 
were not found in any of these cases. From the findings at operation 
and from the subsequent histories of the fatal cases' there was evidence 
of extensive local and abdominal metastasis. 

Clinical characteristics. — The striking feature of the preoperative 
history is its resemblance to the history of the ordinary fibroid case 
and the entire absence of any points in the history or physical examina- 
tion which make it possible to suspect malignancy except in those cases 
in which the extension is so far advanced as to make operative cure or 
any other cure impossible. 

In the first group 2 patients only were living without recurrence, 
one seven, and one four months. One of these patients had the small- 



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MALIGNANT MYOMAS 369 

est tumor of the group, 2 cm. in diameter; it was interstitial in loca- 
tion, without macroscopic evidence of infiltration, and it had the 
smallest number of mitotic figures of any of the tumors included in the 
group, 2200 to the cubic millimeter. The other patient reported 
no signs of recurrence four months subsequent to operation. The 
tumor in this case was large, subserous, pedunculated, 17 cm. in 
diameter, and adherent to the omentum. Not including the very 
small tumor just mentioned there were 2 cases in which the tumors 
were located interstitially; they showed no definite macroscopic 
evidence of infiltration beyond the uterine body. Both of these, 
however, recurred and were fatal. 

As compared with other types of malignant tumors nonepithelial 
uterine tumors are said to be comparatively low grade in malignancy. 
This seems to be true in so far as metastasis in distant organs is con- 
cerned. In the present series definite indication of distant metastasis 
was not found in any case. But from the standpoint of rapid and 
extensive infiltration these tumors must be classified as extremely 
malignant. 

A comparison of the ages of the patients in the different groups 
of the series at the time of operation shows that as a group the patients 
with very malignant tumors averaged §fty years, while all the others 
averaged forty and one half years. The patients in Group 2, with 
the border-line tumors, averaged forty-one years. A rapidly growing 
tumor at or after menopause is very suggestive of this type of 
malignancy. 

Treatment. — Five cases in this series were treated postoperatively 
with the x-ray and radium, but the after-histories indicate that no 
cures were accomplished in those cases in which the operative and 
microscopic examinations indicated extreme malignancy. One case 
(Case 18) is of special interest in this connection. The tumor micro- 
scopically belonged to the group of border-line or transition tumors 
having 800 mitotic figures to the cubic millimeter; at operation such 
extensive adhesions were found that the tumor could not be removed. 
The patient was given prolonged x-ray and radium treatment. After 
two and one half years she is alive and apparently well with some 
regression of the tumor. 

The present plan of surgically removing all uterine fibroids of 
appreciable size seems to be the procedure of choice. The low opera- 
tive mortality figures which are shown by the work of skilled surgeons 

'19— 24 



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370 NEWTON EVANS 

in the better hospitals are an argument in favor of the operative 
method. 

In the present series of 72 cases there were no operative deaths. 
This remarkable absence of fatalities in a group of cases of so serious 
a nature must be looked on in a degree as accidental as is indicated 
by the usual operative mortality percentages in operations for fibro- 
myomas. 

Terminology. — Several different names have been used to designate 
the malignant non-epithelial tumors of the uterus of the type discussed. 
Among these may be mentioned "sarcoma," "myosarcoma," "myoma," 
"sarcomatodes," "leiomyosarcoma," "myoma malignum," "malig- 
nant," "leiomyoblastoma," "malignant leiomyoma," and "malignant 
myoma." In the interest of a uniform terminology it seems well to 
use the term "malignant myoma." 

SUMMARY 

There is evident need of the establishment and recognition of his- 
tologic standards of malignancy in the classification of the non-epithe- 
lial uterine tumors. 

In the present study the only single constant microscopic evidence 
of definite malignancy is the presence of large numbers of mitotic 
figures. 

Many of these tumors have numerous large giant cells with mul- 
tiple hyperchromatic nuclei which are often looked on as evidence 
of malignancy, but they do not contain mitotic figures. There is no 
evidence that such tumors are malignant. 

In the less malignant tumors not containing numerous mitotic 
figures there are morphologic evidences of division of tumor cells 
by direct cell division. 

Clinically the majority of patients with definitely malignant tumors 
present themselves for treatment about the climacteric or later. 
The tumors are difficult to distinguish in the earlier stages from ordi- 
nary fibromyomas, they are not cured by x-ray or radium, and the 
surgical removal of all fibroids of any appreciable size seems to be the 
best treatment. 

Note 1. — The computation to determine the number of mitotic 
figures in a cubic millimeter of tumor tissue: Diameter of oil immersion 



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MALIGNANT MYOMAS 371 

field — 0.170 mm., radius 0.085 mm., area of one field — (3.1416 times 
the square of the radius) 0.022698 sq. mm. Taking the average 
thickness of section as 0.011 mm., the cubic contents of one micro- 
scopic field would be 0.000249678 c. mm., or approximately 0.00025 
c. mm., or 14000 of 1 c. mm. Therefore, having determined the 
number of mitotic figures in 100 fields the number in a cubic milli- 
meter would be 4000 times the average number in one field or 40 
times the number in 100 fields. 

Note 2. — A vaginal myomectomy. At first operation the malig- 
* nancy was not discovered, but it was discovered at a second operation 
following recurrence. 

Note 3. — At first operation a subtotal abdominal hysterectomy was 
done; the malignancy was not recognized. A second operation was 
done because of recurrence. 

Note 4. — In this case the removal of the tumor mass was not 
accomplished, but was discontinued before completion. A tube was 
left in the abdominal wound to facilitate radium treatments, of which 
the patient subsequently had a number; x-ray treatments were also 
given. The patient was alive at the end of one year. 

Note 6. — The patient died three and one half months after the 
hysterectomy from an acute peritonitis, following a cholecystectomy; 
the death had no relation to the previous condition. 

Note 6. — Fragments only removed. Tumor regarded as inoper- 
able and not removed. 



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372 



NEWTON EVANS 





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374 



NEWTON EVANS 



Table 2. — Frequency of Non-epithelial Malignant Uterine Tumors as Com- 
pared with Frequency of Fibroids 



Proper and Simpson 

Miller 

Lewis 

Olshausen 

Kelly and Noble 

Winter 

Winter 

Noble. 

Kelly and Cullen 

Martin i 

Fehling 

JBroun, Woman's Hosp., N. Y. . ' 
Warner 

i 

Geist i 

Present series 

1917-1918 

I 

1906-1918 



Fibroids 

357 
9750 
1518 
6470 
2274 

500 J 

253 

337 
1400 

205 

409 
1500 

100 

250 

968 

3297 



Malignant 




Percentage 




22 


6.00 
1.96 
1.40 
1.30 
2.00 
3.20 
4.30 




2 


0.60 




17 


1.20 




4 


1.90 




8 


1.90 




7 


0.40 


Including all "cellular' 


' 7 


7.00 


"Sarcomas" only, 


2 


2.00 




12 


4.80 


Group 1 


• 


0.62 


Groups 1 and 2 


12 


1.25 


Groups 1, 2, and 3 


38 


4.00 


Group 1 


13 


0.39 


Groups 1 and 2 


22 


0.67 



Table 3. — Mortality Percentages for Consecutive Operations for Removal 
of Fibroids of the Uterus 

Cases Mortality, 
per cent 

Woman's Hospital, New York (Broun) 1500 1 . 86 

Woman's Hospital, New York (1918) 262 1 .53 

Deaver 750 1 .73 

Frank and Brettauer 400 1 .75 

St Mary's Hospital (Mayo Clinic, 1916, 1917, 

and 1918) 1188 1.18 

St. Mary's Hospital (1912-1918) 2774 1 .59 

BIBLIOGRAPHY 

1. Broun, L.: A review of the uterine myomata operated on at the Woman's Hos- 
pital during 1918, comprising 262 cases. Am. Jour. Obst., 1919, lxxix, 333-343. 

2. Deaver, J. B.: Operative treatment of fibromyomatous uterine tumors. Jour. 
Am. Med. Assn., 1916, lxvii, 1216-1218. 

3. Ewing, J.: Neoplastic Diseases. Philadelphia, Saunders, 1919, 1027 pp. 

4. Fehling: Quoted by Kelly and Cullen. 

5. Frank and Brettauer: Quoted by Brown. 

6. Fullerton, W. D.: Uterine sarcoma. Surg., Gynec. and Obst, 1914, xix, 711-718. 

7. Geist, S. H.: The clinical significance of sarcomatous change in uterine fibro- 
myoma. Am. Jour. Obst., 1914, lxix, 766-778. 



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MALIGNANT MYOMAS 875 

8. Gessner: Quoted by Kelly and Cullen. 

9. Jacobi, M. P., and Wollstein, M.: A case of myosarcoma of the uterus. Am. 
Jour. Obst., 1902, xlv, 218-223. 

10. Kelly, H. A., and Cullen, T. S.: Myomata of the Uterus. Philadelphia, Saun- 
ders, 1909, 723 pp. 

11. Kimura, N.: The effects of x-ray irradiation on living carcinoma and sarcoma 
cells in tissue cultures in vitro. Jour. Cancer Research, 1919, iv, 95-135. 

12. Lewis: Quoted by Geist. 

13. Lockyer, C: Fibroids and allied tumors. London, Macmillan, 1918, 604 pp. 

14. Mallory: Principles of pathologic histology. Philadelphia, Saunders, 1914, 
677 pp. 

15. Maroney, W. J.: Sarcomatous change in uterine fibroids. Am. Jour. Obst., 
1916, lxxiv, 445-450. 

16. Meyer: Quoted by Strong. 

17. Martin, A. : Quoted by Noble. 

18. Miller, J. R.: The relation between sarcoma and myoma of the uterus and its 
bearing on *-ray therapy of uterine myomata. Surg., Gynec. and Obst., 1913, xvi, 
315-321. 

19. Mortality statistics, 1916, Seventeenth Annual Report. Washington, 1918, 
46-47. 

20. Noble: Fibroid tumors of the uterus. Jour. Am. Med. Assn., 1906, xlvii, 
1881-18§6; 1998-2003; 2065-2068. 

21. Olshausen: Quoted by Geist. 

22. Pick, L.: Zur Histogenese und Classification der Gebarmuttersarcome. Arch. 
f . Gynak., 1894, xlviii, 24-79. Zur Lehre vom Myoma sarcomatosum und liber die soge- 
annten Endotheliome der Gebarmutter. Arch. f. Gynak., 1895, xlix, 1-29. 

23. Proper, M. S. and Simpson, B. T.: Malignant leiomyomata. Surg., Gynec. and 
Obst., 1919, xxix, 39-44. 

24. Ritter: Ueber das Myosarkom des Uterus. Inaug. Dissert., Berlin, 1887. 

25. Strong, L. W.: The morphology and histogenesis of stromatogenous uterine 
neoplasms. Am. Jour. Obst., 1915, lxxi, 230-248. 

26. Virchow: Die krankhaften Geschwulste. Quoted by Kelly and Cullen. 

27. Warner, F.: Malignant leiomyomata of the uterus. Am. Jour. Obst., 1917, 
lxxv, 241-250. 

28. Weir, W. H.: Muscle-cell sarcomata of the uterus. Am. Jour. Obst., 1901, 
xliii, 618-629. 

29. Williams, J. W.: Contributions to the histology and histogenesis of sarcoma of 
the uterus. Am. Jour. Obst., 1894, xxix, 721-764. 

30. Wilson, £. B. : The cell in development and inheritance. London, Macmillan, 
1911,483 pp. 

31. Winter: Quoted by Broun. 

32. Zacherl, H. : Beitrag zur Kasuistik der Wandsarkome des Uterus. Wien. klin. 
Wchnschr., 1913, xxvi, 1271-1274. 



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STUDIES ON ORGAN TRANSPLANTATION 

TRANSPLANATION OF THE THYROID GLAND WITH INTACT 
BLOOD SUPPLY* 

K. KAWAMURA 



There are two methods of free grafting of a gland: the transplanta- 
tion of pieces of tissue, and the transplantation of the whole organ 
with anastomosis of its blood vessels to those of the same jjerson or 
of another person. In 1892 von Eiselsberg transplanted the thyroid 
gland in a cat. He removed half of the gland and transplanted it 
into the abdominal wall. Several weeks later he extirpated the 
other half of the gland. The animal remained in good conditftm but 
died when the transplanted thyroid was removed. Since that time 
many instances of thyroid grafting, both experimental and clinical, 
have been reported, and it has been shown that thyroid grafts in 
animals take and functionate. 

Fairly effective results were obtained by Cristiani (1904, 1906) after transplantation 
of thyroid tissue in the subcutaneous cellular tissue, by Payr (1906) after transplanta- 
tion in the spleen, and by Kocher (1914) after transplantation in the bone marrow. On 
the other hand, there are also many reports of negative results. Enderlen considered the 
functional activity of transplanted thyroid limited and temporary, as a consequence of 
his experiments in which cats and dogs died even after a period of six months. Bircher, 
Leichner and Kohler, Stieda, and others implanted thyroid gland into the subcutaneous 
tissue or bone marrow of patients, with no permanent improvement. In 1914 von 
Eiselsberg reported the transplantation of thyroid and parathyroid in man. It seemed 
to him at first that the grafting was effective, but all efforts finally proved unavailing. 
He believes that the function of the transplanted pieces of glands is probably only 
temporary. 

The development of vascular surgery has made it possible to transplant whole 
organs with their related vessels. In 1905 Carrel and Guthrie extirpated the thyroid 
gland of a dog, placed it in isotonic salt solution for a few minutes, and replaced it 
into the neck, anastomosing the blood vessels but with reversal of the circulation. The 
arterial blood entered the gland through the thyroid vein and the venous blood flowed 
from the gland to the jugular vein through the thyroid artery. Eleven days after he 
operation an exploratory opening of the neck was made. The color and consistency 
of the gland were normal. Eight months after the operation the gland was normal in 

* Reprinted from Jour. Exper. Med., 1919, xxx, 45-«3. 

376 



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STUDIES ON ORGAN TRANSPLANTATION 377 

size and consistency. Later, Carrel (1909) extirpated a large parenchymatous goiter 
in a dog and replanted it. He then cut transversely the common carotid and united 
its central end to the peripheral end of the internal jugular. The central end of the 
jugular was sutured to the peripheral end of the carotid. The size of the gland increased 
enormously. At the same time, clear fluid exuded from the surface of the gland but 
diminished and stopped completely after more than a week. 

Stich and Makkas performed a series of thyroid transplantations. After the dis- 
section of the upper thyroid artery to the point o» its departure from the common 
carotid, they resected a rhomboid flap of the carotid in connection with the thyroid 
artery and inserted it in the corresponding hole of the other carotid. The internal 
jugular vein was cut transversely just beneath its union with the lower thyroid vein, 
and sutured with the external jugular vein by end-to-side or end-to-end anastomosis. 
At the same time the other half of the gland was extirpated to obtain, immediately, 
sufficient function for the transplanted thyroid. Of three autoplastic transplantations, 
two were positive; that is, fifty-one and two hundred and forty-five days respectively 
after the operation the circulation was intact and the gland, both macroscopically and 
microscopically, was normal. 

The gland was transplanted seven times homoplastically, but no positive result 
was obtained. An obstruction was almost always found at the point of the venous 
anastomosis, which brought about necrosis and reabsorption of the gland. 

Borst and Enderlen similarly transplanted the thyroid of dogs and goats. Their 
method differed somewhat from the procedure employed by Stich and Makkas in that 
. they used, for the grafting of the thyroid artery, the complete segment of the carotid 
with the thyroid artery. In seven instances they extirpated the thyroid and replanted 
it in the same animal. In two of the seven animals (twenty and one hundred 
twenty-two days after operation) the glands were in good condition. In the other 
animals necrosis, hemorrhagic infarct, degenerative metamorphosis, and so forth, 
took place, due to the thrombosis of the thyroid vein. They attempted homoplastic 
transplantation seven times (in dogs and goats), but none was successful. They also 
attempted in three instances to transplant the thyroid from man to man by the em- 
ployment or blood vessel sutures. The upper pole of the gland was transplanted into 
the axilla of the elbow. The results in every case were fruitless. 

Goodman also investigated this problem. He made a bi terminal suture of a seg- 
ment of the attached carotid of the severed vessel of the host, and an end-to-end suture 
of the thyroid vein with the central end of the external jugular of the opposite side. 
He performed three autoplastic and twenty-seven homoplastic transplantations, 
and observed them from twenty-four hours to one hundred twelve days after the 
operation. In autoplastic transplantation he succeeded in two instances (the duration 
of life was four and twenty-three days repsectively) in retaining the thyroid gland in 
its normal state; while in homoplastic transplantation the gland remained intact for 
a short time only, and then showed evidence of absorption. 

The results of the investigations with regard to thyroid transplanta- 
tion as reviewed in the literature did not seem uniform and we were 
therefore induced to investigate the problem further. We chose for 
our experiments the transplantation of the gland through blood 
vessel sutures because of the favorable restoration of the circulation 
of the gland by this method. 



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378 k. kawamura 

Experiments 

All the experiments were performed on dogs. Since the relation 
of the thyroid to its vessels in the dog is different from that in man, 
it may be well briefly to note this difference before the technic is 
described. In a dog the glands are spindle-shaped, situated beside 
and beneath the larynx, usually separated from each other, and more 
or less covered with muscle. The dog, especially the bulldog, has a 
relatively large thyroid, which is not always propoitional to the size 
of the animal; a small dog may have remarkably large glands due to 
the development of the so-called colloid goiter. The arterial blood 
reaches the gland mainly through the superior thyroid artery, which 
arises from the common carotid and enters the gland at its upper 
pole after having made an upward convex curve. Very rarely this 
artery enters the gland near its middle and ramifies with many 
branches. The inferior thyroid artery is very small; accordingly it 
may usually be ignored in the transplantation of the thyroid. The 
venous blood flows out through two veins, the superior and inferior . 
thyroid veins. The superior thyroid vein leaves the upper pole of the 
gland and empties into the internal jugular vein, while the inferior 
thyroid vein, consisting of two stems, opens into the same vein further 
down. The diameter of the superior thyroid artery and thyroid 
veins is scarcely greater than 1.5 to 2.5 mm. It is, therefore, almost 
impossible to anastomose these vessels. 

The operation was performed under intratracheal ether anesthesia. 
The Carrel (1907) technic of blood vessel suturing was employed, 
and special attention was paid to rigid asepsis. A longitudinal median 
incision was made in the neck and the superficial muscles were sepa- 
rated. The thyroid gland was dissected from the surrounding tissue, 
the superior thyroid artery and superior and inferior thyroid veins 
being left intact. In most instances the gland was extirpated with 
a portion of the internal jugular vein and a segment of the common 
carotid artery, connecting the thyroid veins and the superior thy- 
roid artery respectively. The gland was immediately wrapped in a 
sponge saturated with warm salt solution. After a few minutes the 
gland was transplanted to the other side of the neck of the same dog, 
or into the neck of another dog, where the thyroid had been pre- 
viously removed. The segment of common carotid was inserted in 
the place of the other below the point of outlet of the thyroid artery. 



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STUDIES ON ORGAN TRANSPLANTATION 379 

The peripheral end of the internal jugular vein was united to the cen- 
tral end of the internal or external jugular vein of the recipient by 
end-to-end anastomosis. In one case the gland with a rhomboid 
flap of the carotid at the point of outlet of the superior thyroid artery 
was removed (Stich's so-called patching method) and replaced in the 
wound in the neck. In two animals the peripheral end of the inter- 
nal jugular vein was united to the wall of the external jugular vein 
(end-to-side). Moreover, in 2 cases, after resection of half of the 
spleen, the thyroid was transplanted to the splenic vessels of the same 
animal. In these instances the superior thyroid artery was sutured to 
the splenic artery, and the internal jugular vein to the splenic vein 
by end-to-end anastomosis. The time required for the extirpation 
of the gland and its complete transplantation was usually from one to 
two hours. The clamp on the vein was removed first and then that 
on the artery. As soon as the clamps were unfastened the gland be- 
came normal in color; it was somewhat distended. Several days after 
the operation the wounds were opened and the condition of the trans- 
planted thyroid gland was examined. As a rule, if the gland appeared 
normal the other intact thyroid was fixed in 10 per cent formal- 
dehyde for microscopic examination. 

Both autotransplants and homotransplants of the gland were 
made, as shown in Table 1. A total of eight autoplastic and seven 
homoplastic transplantations was made. Two autoplastic trans- 
plants (Experiments % and 3) and one homoplastic (Experiment 9) 
are described. 



Experiment 2 (Dog 2).— Adult bulldog, mule; weight 12 kg. 

Sept. 18, 1918. Placed under ether anesthesia and the right thyroid gland trans- 
planted to the left side of the neck. The segment of the right carotid artery, from which 
the superior thyroid artery arose, was implanted by end-to-end anastomosis into the 
left carotid. .The peripheral end of the right internal jugular vein was anastomosed to 
the cardial eud of the left external jugular vein. The excised gland had been left in 
a salt pack for a short time. After the removal of the clamps the pulsation of the 
superior thyroid artery was very evident and the circulation through the gland was 
reestablished so that it immediately became normal in color. The extirpation of the 
gland and its complete transplantation occupied one and one-half hours. The 
wound was closed according to the routine technic of the laboratory. 

September 20. The animal was in good condition and had a normal appetite. 

October 9. Second operation. The weight of the animal at this time was 13.1 
kg. The transplanted thyroid appeared perfectly normal. The intact left thyroid 
was removed. The animal recovered from the operation and showed no signs of 
tetany. 



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380 



K. KAWAMURA 




Fig. 192. — Photomicrograph of intact left thyroid of Dog 2 ( X70). 








Fig. 193. — Photomicrograph of transplanted right thyroid of Dog 2 (autotransplant). 
Compare with the control in Fig. 192 ( X70). 



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STUDIES ON ORGAN TRANSPLANTATION 



381 




Fig. 194. — Photomicrograph of intact right thyroid of Dog 3 (X70). 

■MM 




Fig. 195. — Photomicrograph of transplanted left thyroid of Dog 3 (autotransplant) 
Compare with the control in Fig. 195 ( X70). 



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382 K. KAWAMURA 

October 29. The animal died early in the morning (forty-one days after the first 
operation and twenty days after the second). 

Necropsy. — Performed shortly after death. The wound had healed completely; 
the cause of death could not be found. The transplanted thyroid was normal in size, 
color, and consistency and appeared normal on section. The capsule of the gland was 
not markedly thickened. The implanted blood vessels were patent. The lines of 
union were covered with epithelium and so smooth that they were found with difficulty. 

Microscopic examination. — The transplanted thyroid showed no difference from the 
control gland. The capsule of the gland was not increased in thickness. The follicles 
were normal in size and about the same in both the central and peripheral parts of the 
gland; they were lined with cuboidal epithelium, and filled with a normal amount of 
colloid. The staining reaction was normal; mitoses were not present. The interstitial 
connective tissues were not increased as compared with the control specimen. Increase 
of blood vessels was not visible. No leukocytic infiltration could be found (Figs. 192 
and 193). 

Experiment 3 (Dog 3). — Adult collie, female; weight 21.3 kg. 

Sept. 19, 1918. Etherized and the left thyroid gland transplanted to the right side 
of the neck. The gland was small, as was also the internal jugular vein. The left 
thyroid was displaced to the right with a segment of the common carotid and the in- 
ternal jugular vein. The segment of the left carotid was inserted into the right carotid. 
The peripheral end of the left internal jugular vein was implanted into the wall of the 
right external jugular by a terminolateral anastomosis. The operation was difficult 
owing to the different sized vessels. Nevertheless, it was, on the whole, satisfactory. 
There was no leakage at the line of suture. The circulation was reestablished about 
one and one-half hours after the extirpation of the gland. The wound was closed in 
the routine manner. 

October 9. Second operation. At this time the animal weighed 21.4 kg. The 
transplanted thyroid gland appeared normal. The intact right thyroid was removed 
and fixed in formaldehyde. 

November 20. The animal died during the preceding night (sixty-two days after 
the first operation and forty-two days after the second). 

Necropsy. — Performed shortly after death. The wound had healed by first inten- 
tion; there were slight adhesions at the site of operation. The transplanted thyroid 
appeared entirely normal. The blood vessels were patent, and the site of anastomosis 
was in excellent condition. The cause of death could not be determined. 

Microscopic examination. — The transplanted thyroid was practically normal. The 
thickness of the capsule of the gland was normal. No difference was seen in the size 
and form of the follicles, in the colloid content, or in the quantity of interstitial connec- 
tive tissue, in comparison with the other gland of the same dog. Cuboidal epithelium 
lined the follicles as in the control section. The gland contained a large number of 
blood vessels. Here and there clumps of a few leukocytes were visible (Figs. 194 
and 195). 

Experiment 9 (Dog 9). — Adult mongrel, male; weight 5 kg. 

Sept 25, 1918. The left thyroid of another dog was transplanted, under ether 
anesthesia, to the left side of the neck by the insertion of a segment of the common 
carotid into the carotid. After the dissection and removal of the left thyroid gland, 
about 3 cm. of the left common carotid were resected. The peripheral end of the 
internal jugular vein of the donor was united to the central end of the external jugular 
of the recipient. The transplanted thyroid was very large, as was also the internal 
jugular vein. The operation was easily performed. After one and one-quarter hours 



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STUDIES ON ORGAN TRANSPLANTATION 



383 



the circulation through the gland was reestablished satisfactorily. Closure of the 
wound was made as usual. The animal recovered from the operation but developed 
distemper. 

October 1. The animal died during the night. 

Necropsy. — Death due to distemper. Both the arterial and the venous anastomoses 
were in good condition; the caliber of the vessels was well preserved. The transplanted 
thyroid appeared normal in size, color, and consistency. On section it was normal in 
appearance except in the posterior border where the tissue was somewhat brown 
and was more gelatinous than the other part. 




Fig.' 196. — Photomicrograph of transplanted thyroid of Dog 9 (homotransplant) ( X70). 

Microscopic Examination. — The capsule of the gland was more or less thickened. 
The interlobular septum also appeared to be thickened. The size of follicles and their 
colloid content were as well preserved as in the autografts. The staining reaction 
appeared normal. Few follicles contained desquamated cells in their lumen. Some 
of these cells were calcified. There was a small amount of leukocytic infiltration. The 
vascularization of the gland was normal (Fig. 196). 

Eight autoplastic and seven homoplastic transplantations of the 
thyroid gland were performed. In two of the eight autoplastic trans- 
plantations the gland was transplanted to the splenic vessels, in six 
to the neck. The first two dogs were examined by exploratory 
laparotomy twenty-one and twenty-eight days respectively after the 
first operation. It was found that the glands had become necrotic 
because of thrombosis. It seems almost impossible to get successful 



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384 



K% KAWAMURA 



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388 K. KAWAMURA 

results by anastomosing such a small vessel as the superior thyroid 
artery to the splenic artery. Two of the six transplantations to the 
neck were replaced in the same wounds, and four were made to the 
other side of the neck. One of these was examined eighteen days after 
the operation and obstruction of the transplanted vein and necrosis 
of the gland were found. One transplant was examined forty-nine 
days after the operation. The gland had entirely disappeared, and 
the superior thyroid artery and the inferior thyroid vein could not be 
found, though the pulsation of the common carotid was very evident 
throughout. The failure was due to infection of the wound. In 
four instances (one, four, forty-one, and sixty-two days after the 
operation), all blood vessels were patent, and the gland appeared, 
both macroscopically and microscopically, to have preserved its nor- 
mal structure. 

Seven of the homoplastic transplantations were examined in periods 
of five, six, eighteen, twenty-four, twenty-seven, twenty-nine, and 
sixty-three days after the first operation. In two the segments of the 
carotid remained free from thrombosis and were covered smoothly 
with endothelium, although in five instances the transplanted vessels, 
in whole or in part, were occluded. The thyroid gland showed evidences 
of remarkable change in proportion to the time elapsed. Six days 
after the operation the gland retained its original size, and for the most 
part, was translucent, but in a part of the posterior border the tissue 
was beginning to soften. Microscopic examination showed that 
the size of follicles and colloid content were as well preserved as in 
the autograft. In the gland which was examined eighteen days 
after the transplantation, the consistency was markedly soft, the color 
of the section was pale red, and no hemorrhage had occurred at that 
time, notwithstanding the fact that the gland kept its original size and 
the carotid was still patent. Microscopic examination showed great 
degeneration of the gland. After twenty-four days the microscopic 
change of the gland increased, and it became gradually smaller. In 
one case, sixty-three days after the operation, no trace of the gland was 
to be found. In brief, our attempts at homoplastic transplantation 
were unsuccessful. 

DISCUSSION 

Our results in thyroid transplantation by blood vessel sutures agree 
on the whole with the experienes of Stich and Makkas, Borst and Ender- 



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STUDIES ON ORGAN TRANSPLANTATION 389 

len, and Goodman. In the autoplastic transplantations we succeeded, 
as they did, in maintaining the glands for a long time in their original 
shape and structure, and apparently in function. In the series of 
homoplastic transplantations, on the contrary, the transplant remained 
intact for a time, then underwent degenerative changes, and, conse- 
quently, absorption. 

Hesselberg has published a paper concerning a companion of autoplastic and 
homoplastic transplantation of thyroid tissue in guinea pigs. She transplanted pieces 
of glands into the subcutaneous tissue of the abdominal wall and examined them at 
intervals of from twenty-four hours to fifty-two days. In the first stage, com- 
prising the first four to five days, there was no noticeable difference between the auto- 
grafts and the homograf ts. Large parts of both grafts became necrotic in the center, but 
sn the peripheral part only a narrow zone of thyroid tissue was left. In the second 
stage, extending over the next seven days, the differences between the two grafts appeared. 
There was an increase in the number of follicles in the autografts and a corresponding 
decrease in the size of the necrotic central area. In the homograf ts a large number of 
lymphocytes and connective tissue were visible. From the twelfth day on, in the third 
stage, the difference between the grafts was sharply defined. In the autograft the 
regeneration of the thyroid tissue was steadily progressing and nearly completed after 
twenty-one days. In the homograf t, on the contrary, the destruction of the follicles 
progressed with great intensity. 

Loeb (1918-1919) recently designated the transplantation into nearly related 
animals and to the nearly related of the same species as "syngenesioplastic" trans- 
plantation. He carried out transplantation of thyroid from mother to children, from 
sister and brother to sister or brother, and in one instance from child to mother in guinea 
pigs. The results were intermediate between those which Hesselberg obtained after 
autotransplantation and homotransplantation. In most instances the thyroid behaved, 
for a time, like an autotransplanted tissue, but gradually an intensive lymphocytic 
infiltration took place with secondary destruction of the healthy acini. In a smaller 
number of cases the fibrous tissue also was increased, the fibroblasts behaving like those 
i of homoplastic transplantation. 



In one of our cases of homoplastic transplantation also (Experiment 
9) the gland showed indications of degeneration on the sixth day after 
the operation, in spite of the fact that the transplanted blood vessels 
were patent. The destruction of the gland increased in the process 
of time. 

Homoplastic transplantation, however, can be successfully made in 
certain kinds of tissue. At the instant the animal dies the tissues, in 
general, do not lose their vitality in spite of the arrest of the circula- 
tion. On the other hand, individual tissues have a dijfferent power 
with regard to regeneration and repair. Some tissues, such as skin, 
fascia, periosteum, and bone, which survive for a long time under 
the interruption of the circulation, can regenerate and repair easily. 



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S90 K. KAWAMURA 

Such tissues, as is well known, can be transplanted homoplastically 
with success although the ultimate fate of the transplant is not fully 
known. 

As has been noted, the opinions of authors differ with regard to the 
fate of the more highly organized tissues, such as the thyroid gland. 
Cristiani has shown that transplanted and functionating thyroid 
may be kept in good condition in its new location for a long time, 
provided the operation is performed with certain precautions. For 
the successful transplantation, he emphasized that the pieces of gland 
transplanted must be small and numerous, that thyroid tissue from 
the same species only will grow, and that living tissue may be trans- 
planted, provided that not more than ten seconds elapse between the 
extirpation of the tissue and its transplantation. Cristiani applied 
also, clinically, the results of his experimental work, and from his 
experience on patients arrived at the following conclusions: With 
his method of thyroid grafting it is possible to produce new thyroid 
organs which not only retain their vitality and functionate, but 
gradually grow so that small grafts in time become new thyroid 
glands (glandules neothyreoideae) of different sizes. 

Payr (1906) transplanted thyroid gland into the spleen of animals, believing that 
spleen is suitable soil for healing because of its vascular nature. Of 48 experiments of 
autoplastic transplantation, mostly on cats and dogs, he obtained eight promising 
results. The longest duration of the observation was two hundred seventy-one 
days. He had likewise made the transplantation of the thyroid gland clinically. A 
few years ago he reported 7 cases of thyroid transplantation for myxedematous 
patients; they showed marked improvement, but most of them relapsed from three to 
eight years after the operation. He remarked that organic cerebral defects of patients 
cannot be improved by thyroid grafting. 

Kocher reports several favorable cases of transplantation of pieces of thyroid in 
patients, using the bone marrow as new soil. He prefers the tibial metaphysis to the 
spleen on account of the greater ease and safety of the operation and the equally vas- 
cular soil; hemostasia is secured by operating in two stages. With regard to the tissue 
for transplantation: Pieces from exophthalmic goiter are especially desirable, because 
the glands are remarkably vascular with comparatively firm structure, and because 
their proper parenchyma surpasses considerably the supporting substance. He stated 
that there are no grounds for the belief, based on animal experiment, that homoplastic 
transplantation cannot also succeed in man. 

There are some reports of conflicting opinions with reference to these favorable 
results. Bircher implanted pieces of thyroid into the subcutaneous tissue of the 
occipital region in three cretins. After short improvement there was relapse into the 
former state. On histologic examination of the grafts he found that no normal thyroid 
tissue was left, but necrosis and connective tissue had replaced the whole. His observa- 
tions made him skeptical as to the permanent function of homoplastic implanted thy- 
roid. Leichner and Ktihler were of the same opinion as Bircher. Stieda reported 3 



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STUDIES ON ORGAN TRANSPLANTATION 391 

cases in which the grafting was done on myxedematous children who were more or less 
idiotic. After operation they showed signs of remarkable, rapid improvement, which 
shortly came to a standstill. Schaack and M tiller repeatedly transplanted thyroid 
tissue into the bone marrow or into the subcutaneous tissue, with no permanent im- 
provement. The thyroid grafts which Worobjew and Perimow made on a myxedem- 
atous patient healed, but subsequently became smaller and were totally absorbed, von 
Eiselsberg (1914) also, from his experience with patients, expressed doubt that successful 
results could be obtained. 

Thus, while some observers admit the feasibility of thyroid graft- 
ing, others deny it. The negative results of our experiments do not 
warrant denial of the positive results of Ciistiani, Payr, Kocher, and 
others, but, as Bircher has already noted, we should not lightly pass 
over the possibility that implanted pieces of tissue will have an influ- 
ence as long as the colloid exists, that its absorpt ion occurs very slowly, 
and finally, that the moment the colloid is absorbed its influence 
stops. Furthermore, although many successful cases of piecemeal 
homoplastic transplantation on patients have been reported, they are 
not always without objection, because one important factor is wanting 
in all, namely, the subsequent removal and microscopic examination 
of the tissue. In short, for permanent good results we must expect 
to work further in this direction. Several points must be considered 
in the successful take of transplanted tissue: (1) The avoidance of 
injuring the tissue, and a sufficient blood supply. In this connec- 
tion the transplantation with intact blood supply is the better method. 
(2) In the organ transplantation, especially by means of blood vessel 
sutures, aseptic precaution must be observed as rigidly as possible; 
If not, the occlusion of the transplanted vessels or necrosis of the 
organ may easily occur. Concerning asepsis in operations on blood 
vessels Carrel (1907) states: "it seems that the degree of asepsis under 
which general surgical operations can successfully be performed may be 
insufficient for good results in vascular operations." In our first 
case of autoplastic transplantation the results immediately after the 
operation were satisfactory, but the lower part of the wound was, 
unfortunately, slightly infected. At the exploratory opening of the 
neck forty-nine days after the operation, we found that the trans- 
planted common carotid was patent, but that the gland had entirely 
disappeared, due to infection. 

Besides, the rapid work, keeping the gland warm, the avoidance 
of dryness, rough handling, chemical irritation, close contact with the 
new soil, and strict arrest of hemorrhage, are all apparently necessary 



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392 K. KAWAMURA 

conditions for a good transplantation. If these precautions are used 
autoplastic transplantation is almost always successful. • But we 
failed, as did the others, in homoplastic transplantation, notwithstand- 
ing the fact that we used similar care. The factors that may have 
been responsible for the failure are briefly the following: 

It is well known that nerves have some control over the nutrition 
and function of tissues. Raynaud's disease, for example, is supposed 
to be due to spasm of the arterioles, resulting from peripheral neuritis. 
If a nerve trunk is injured severely and the peripheral end undergoes 
degeneration, several phenomena may occur, due to the loss of the 
trophic function of the nerve, such as dryness of the skin, trophic 
ulcers, fragility of the nails and hair, and arthropathies. It seems to 
be reasonable, therefore, to suppose that the failure of the graft can 
be attributed to the section of the nerves which reach the organ. 

Crowe and Wislocki in experimental work on suprarenal glands in dogs attributed 
degenerative changes of the graft to the lack of nerve supply to it. We do not, however, 
fully concur with their opinion. Salzer and others also emphasize the independence 
of grafts from the nervous system. Manley and Marine, in considering the question 
of whether or not secretory nerves were necessary to the gland, experimented on rabbits. 
They have demonstrated that such nerve fibers are not essential in order that thyroid 
tissue may exhibit the characteristic morphologic and physiologic changes known to 
be associated with great variations in functional activity. Other authors have also 
found that thyroid tissue may be readily transplanted in widely distant parts of the 
body. In our experiments on autoplastic transplantation we obtained good results in 
spite of complete dissection and removal of thyroids from their surrounding tissues. 
We cannot therefore consider that the failure of homoplastic transplantation of the 
thyroid is due to the section of its nerves. 

Murphy tried to prove that a homoplastic or heteroplastic graft cannot develop 
indefinitely on its host. He discovered that the power of the organism to eliminate 
foreign tissue is due to organs such as the spleen or bone marrow, and that when these 
organs are less active (by removal of the spleen or the injection of benzol) a foreign 
tissue (tumor) can develop rapidly after it has been grafted. The grafts became 
absorbed from twelve to fifteen days after the transplantation. 

Hesselberg and Loeb attached a peculiar significance to lymphocytic reaction and 
to proliferation of connective tissue. They believe that the destruction of the thyroid 
tissue which occurs after the homograf ting is not caused by a direct primary disintegra- 
tion or the solution of follicles, due to the action of substances circulating in the body 
fluids, but depends on the destructive activity of the lymphocytes, and of the connective 
tissue of the host The former invade the follicles and destroy them directly; the latter 
surrounds and compresses, and thus destroys the follicles. Why do the lymphocytes 
and the connective tissues attack the homograf ts only, and not the autografts? It is 
well known that lymphocytes and connective tissue appear usually as the response to 
the reaction of foreign bodies. They may be commonly discovered around suture 
materials, such as silk and linen thread, that have been used in operations. It is 
reasonable, therefore, to assume that homograf ts which do not take may act as foreign 
bodies. 



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STUDIES ON ORGAN TRANSPLANTATION 893 

The obstacle to success in homoplastic transplantation lies probably in the differences 
of biochemic factors between the animals. As Ullman expresses it, the cell proto- 
plasm, specific for each organism, varies with the individual; there are as many proto- 
plasms as there are individuals; in homoplastic transplantation the appearance in the 
body of a foreign protoplasm calls forth ferments into the circulation which destroy 
the transplanted tissue. 

Stich enumerated the following factors as the cause of the destruction of the grafts: 
primary toxic action of the tissue fluid on transplanted organs; production of an anti- 
body in the organism of the host through foreign albumin; and finally, starvation of 
the transplanted tissue, owing to the incapacity of the assimilation of materials that 
are necessary for its growth. 

We are still ignorant of the means of eliminating these factors. Lexer (1914) 
showed that he had succeeded in overcoming some of the biochemic reactions between 
his animals by prolonged preliminary treatment of the host with tissues and blood 
serum taken from the donor. He considered that the possibility of the' improvement 
of homoplastic surgery was most hopeful along this path. Schbne believes that positive 
results may be obtained in animals through the same nourishment and the same mode 
of living for a long period of time. Sauerbruch and Heyde demonstrated that direct 
communication of blood vessels was proved between parabiotic rabbits, and that sub- 
stances which are soluble in blood, iodin, strychnin, and so forth, and even bacteria, go 
from one animal to the other through newly formed vascular channels. The question of 
whether or not products of metabolism of one animal are pernicious to another has not 
been solved. Enderlen and his collaborators aimed to make the biochemic differ- 
ences equal by direct blood vessel anastomosis in dogs, but they could not attain their 
object. In short, it seems to be most important to discover the method of equalizing 
as nearly as possible biologic differences between donor and recipient. 

CONCLUSION 

Our experiments on dogs showed that the thyroid gland which was 
autoplasticaUy transplanted, by means of various methods of blood 
vessel anastomosis, could live in good condition and functionate fav- 
orably several months after the operation, even after the interruption 
of the circulation for one and one-half hours. They further showed 
that the circulation through the transplanted blood vessels as well 
as glands was as good as normal, and that permanent successful results 
of the homoplastic transplantation of the gland are as yet not possible. 

BIBLIOGRAPHY 

1. Bircher, £.: Zur Implantation von Schilddrusengewebe bei Kretinen. Deutsch. 
Ztschr. f. Chir., 1909, xcviii, 75-88. 

2. Borst and Enderlen: Ueber Transplantation von Gef assen und ganzen Organen. 
Deutsch. Ztschr. f. Chir., 1909, xcix, 54-163. 

3. Carrel, A.: The surgery of blood vessels, etc. Bull. Johns Hopkins Hosp., 1907, 
xviii, 18-28. 

4. Carrel, A.: Results of the transplantation of blood vessels, organs and limbs. 
Jour. Am. Med. Assn., 1908, li, 1662-1667. 



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394 K. KAWAMURA 

5. Carrel, A.: Thyroid gland and vascular surgery. Surg., Gynec. and Obst., 1909, 
viii, 606-612. 

6. Carrel, A.: The transplantation of organs. New York Med. Jour., 1914, xcix, 
839-840. 

7. Carrel, A. and Guthrie, C. C: Extirpation et replantation de la glande thyroide 
avec reversion de la circulation. Compt. rend. Soc. biol., 1905, lix, 413. 

8. Cristiani, H.: La greffe thyroldienne chez l'homme. Semaine med., 1904, xxiv. 
81-83. 

9. Cristiani, H. and Kummer, E.: Ueber funktionelle Hypertrophic tiberpflanzter 
Schilddrusensttickchen beim Menschen. Miinch. med. Wchnschr., 1906, liii, 2377- 
2380. 

10. Crowe, S. J. and Wislocki, G. B. : Experimental observations on the suprarenal 
glands with especial reference to the functions of their interrenal portions. Bull. Johns 
Hopkins Hosp., 1914, xxv, 287-304. 

11. von Eiselsberg, A.: Uebpr erfolgreiche Einheilung der Katzenschilddrlise in die 
Bauchdecke und Auf treten von Tetanie nach deren Exstirpa tion. Wien. klin. Wchnschr. , 
1892, v, 81-85. 

1 2. von Eiselsberg, A. : Zur FVage der dauernden Einheilung verpflanzter Schilddrusen 
und Nebenchilddrilsen, zugleicb ein Beitrag zur post-opera tiven Tetania parathyreo- 
priva. Arch. f. klin. Chir., 1915, cvi, 1-15. 

13. Enderlen: Untersuchungen tlber die Transplantation der Schilddrtise in die 
Bauch hohle von Katzen und Hunden. Mitt. a. d. Grenzgeb. d. Med. u. Chir., 1898, iii, 
474-531. 

14. Enderlen, Hotz, and Flbrcken: Ueber Parabioseversuche durch direkte Gefass- 
vereinigung. Beitr. z. klin. Chir., 1910, lxx, 1-19. 

15. Goodman, C: The transplantation of the thyroid gland in dogs. Am. Jour. 
Med. Sc., 1916, clii, 348-355. 

16. Hess, J. H. and Strauss, A. A.: Autotransplantation and homotransplantation of 
the thyroid gland using the thyroid capsule as the seat of transplantation. Arch. Int. 
Med., 1917, xix, 518-528. 

17. Hesselberg, C: A comparison of autoplastic and homeoplastic transplantation 
of thyroid tissue in the guinea-pig. Jour. Exper. Med., 1915, xxi, 164-178. 

18. Hesselberg, C. and Loeb, L. : Successive transplantation of thyroid tissue into 
the same host. Jour. Med. Research, 1918, xxxviii, 33-53. 

19. Kocher, T.: Ueber die Bedingungen erfolgreicher SchilddrUsentransplantation 
beim Menschen. Arch. f. klin. Chir., 1914, cv, 832-914. 

20. Lcichner, H. and Kohlei, R.: Ueber homoioplastische Epithelkorperchen- und 
Schilddrusenverpflanzung. Arch. f. klin. Chir., 1910-1911, xciv, 169-185. 

21. Lexer, E.: Ueber freie Transplantationen. Arch. f. klin. Chir., 1911, xcv, 827- 
851. 

22. Lexer, E. : Die freie Transplantation. International Society of Surgery, Fourth 
Congress, New York, April 15, 1914. Free transplantation. Trans, by Lederer, M. 
Ann. Surg., 1914, lx, 166-194. 

23. Loeb, L. : Syngenesioplastic transplantation of the thyroid in the guinea-pig. 
Jour. Med. Research, 1918-1919, xxxix, 3^-57. 

24. Loeb, L.: Multiple transplantations of the thyroid and the lymphocytic re- 
action. Jour. Med. Research, 1918-1919, xxxix, 71-91. 

25. Manley, O. T. and Marine, D.: Studies in thyroid transplantation. I. Data 
relative to the problem of secretory nerves. Proc. Soc. Exper. Biol, and Med., 
1914-15, xii, 202-204. 

26. MUller: Kretinismus. Deutsch. med. Wchnschr., 1914, xl, 989. 



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STUDIES ON ORGAN TRANSPLANTATION 395 

27. Murphy, J. B.: Factors of resistance to heteroplastic tissue-grafting. Jour. 
£xper. Med., 1914, xix, 513-522. 

28. Payr, E.: Transplantation von Schilddrusengewebe in die Milz; experimented 
und klinische Beitrage. Arch, f . klin. Chir., 1906, lxxx, 7SO-826. 

29. Payr, E.: Zur Frage der SchilddrUsen transplantation. Arch. f. klin. Chir., 
1915, cvi, 16-30. 

30. Salzer, H.: Zur Frage der Schilddrilsentransplantation. Arch. f. klin. Chir., 
1909, lxxxix, 881-911. 

31. Sauerbruch, F. and Heyde, M.: Ueber Parabiose klinstlich vereinigter Warm- 
bl titer. Mttnch. med. Wchnschr., 1908, lv, 153. 

32. Schaack: SchilddrUseneinpflanzungen in das Knochenmark oder Unterhaiitfett- 
gewebe. Deutsch. med. Wchnschr., 1914, xl, 989. 

33. Schone: Transplantationsversuche mit artgleichen und artfremden Geweben. 
Deutsch. med. Wchnschr., 1911, xxxvii, 908. 

34. Stich, R.: Ueber den heutigen Stand der Organtransplantationen. Deutsch. 
med. Wchnschr., 1913, xxxix, 1865-1868. 

35. Stich, R. and Makkas, M.: Zur Transplantation der Schilddruse mittels Gefass- 
naht. Beitr. z. klin. Chir., 1908, lx, 431-449. 

36. Stieda: Einpflanzung von Schilddrusengewebe. Deutsch. med. Wchnschr., 
1914, xl, 988. 

37. Ullman, E.: Tissue and organ transplantation. Ann. Surg., 1914, lx, 195. 

38. Worobjew, W. N. and Perimow, W. A.: Ein Fall von angeborenem familiarem 
Myxbdem. Versuch von Transplantation der Schilddruse. Zentralb. f. Chir., 1914. 
xli, 920. 



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ISOLATION OF THE IODIN COMPOUND WHICH OC- 
CURS IN THE THYROID* 

First Paper 

E. C. KENDALL 



Received for publication, June 10, 1919. 

Despite the many years of investigation of the thyroid, some 
of the most fundamental problems concerning this ductless gland 
are still the subject of speculation and controversy, and the 
certain progress which follows quantitative knowledge has not yet 
materialized. Since quantitative values cannot be obtained by 
clinical observations alone, and since pathologic studies of the glands 
cannot of themselves solve the function of the thyroid, it becomes 
apparent that nothing short of the actual isolation in pure 
crystalline form of the chemical substance or substances within the 
gland, which are responsible for its activity, can furnish the necessary 
knowledge with which to gain quantitative relationship. Having 
accomplished the isolation in pure crystalline form of the active 
agents within the gland, quantitative results may be obtained and 
ultimate solution of the thyroid problem is within the power of the 
investigator. 

INVESTIGATION OF THE CHEftflCAL CONSTITUENTS OF THE GLAND, 

WITH ISOLATION OF THE IODIN-CONTAINING COMPOUND IN 

PURE CRYSTALLINE FORM 

Starting with fresh and desiccated thyroid the present investi- 
gation was at first concerned with the diffusibility of the iodin- 
containing compound. Iodin is not dialyzable from the thyroid 
proteins, and will withstand rather severe chemical treatment and 
still be undialyzable through a collodion sack in running water. In 
order to determine the stability of the iodin compound, various 

* No historical review of the chemical investigation of the thyroid is given in this 
paper. The reader is referred to the attached bibliography. 
Reprinted from Jour. Biol. Chem., 1919, xxxix, 125-147. 

396 



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ISOLATION OF THE IODIN COMPOUND 397 

hydrolytic processes were applied to the thyroid proteins. Among 
others the alcoholic alkaline hydrolysis used by Vaughan was tried 
and, with some slight modifications, was found to produce a deep 
seated hydrolysis without breaking off iodin from its organic combina- 
tion. Furthermore, the hydrolysis so alters the iodin-containing 
compounds that about 70 per cent of the total iodin is dialyzable. 
Another change brought about by the hydrolysis is the solubility 
of the iodin compound in acid. About 50 per cent of the total iodin 
contained in the hydrolyzed products is soluble in acids, and 50 per 
cent is insoluble. The iodin in the acid-insoluble portion is to a 
large extent not dialyzable. The presence of iodin in organic combina- 
tion and in non-dialyzable form was encouraging evidence of the 
stability of the iodin compound and invited further investigation. 

The physical and chemical properties of the acid-insoluble group 
of hydrdlyzed constituents will be described somewhat in detail, 
since this will bring out the chemical problems involved and some of 
the difficulties encountered. 

An alkaline solution of the acid-insoluble constituents is dark 
brown, almost black, with a green fluorescence, and shows a TyndaU 
phenomenon with a beam of light. The non-diffusibility, fluorescence, 
and Tyndall phenomenon show that the solution is one of colloidal 
nature. Among the acid-insoluble constituents are fatty acids result- 
ing from the original fat in the desiccated thyroid, and sulfur, which 
results from the decomposition of cystin. The solution has no charac- 
teristic odor other than a general fatty smell. The first step in the 
method of separating the iodin compound is to dry the acid-insoluble 
constituents, mix with infusorial earth, and extract with petroleum 
ether to remove fatty acids and sulfur. 

Later it was found that fresh thyroid glands could be substituted 
for desiccated thyroid as a source of material, and that hydrolysis in 
alcohol was not necessary. Hydrolysis of the proteins may be carried 
out by use of aqueous sodium hydroxid alone, and the length of the 
time can be reduced to twenty-four hours. A quantitative separation 
of all fats, as the sodium soap may be effected, and a perfectly clear 
alkaline filtrate of the hydrolyzed thyroid proteins containing practi- 
cally the entire iodin content of the gland is obtained. On acidification 
of this solution, a fine flocculent precipitate separates. If this precipi- 
tate is filtered off and dried, it is found to contain approximately 0.1 
per cent of the total weight of the fresh glands used. It contains, on 



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398 E. C. KENDALL 

the average, 26 per cent of the total iodin. The total iodin in the 
gland, therefore, is divided by aqueous alkaline hydrolysis into acid- 
soluble and acid-insoluble compounds. Approximately three-fourths 
of the total iodin-containing compounds are soluble in acid and only 
one-fourth insoluble. This proportion is remarkably constant during 
.different times of the year, and in different samples of thyroid from 
various species. The significance of the figure is not entirely clear, 
but in all probability it represents the equilibrium existing within the 
glands between the completed iodin compound which possesses 
physiologic activity and the materials which are used by the gland 
in the building up of the substance. Physiologically tested, the acid- 
soluble hydrolyzed constituents are inactive, and the small portion 
which is precipitated by acid possesses the entire physiologic activity 
of the gland. 

The solubility of the acid-insoluble iodin compounds in organic 
solvents varies, depending on the solvent used, the presence of water, 
whether or not acid is present, and the temperature. About 10 per 
cent of the total iodin is soluble in ethyl ether, but only a small amount 
is soluble in petroleum ether. 

If desiccated thyroid has been used as a source of material the 
dry acid-insoluble products freed from fatty acids by extraction with 
petroleum ether are dissolved in sodium hydroxid and again acidified. 
If the aqueous hydrolysis has been used the precipitate obtained by 
acidifying the alkaline solution of hydrolyzed products is dissolved in 
sodium hydroxid and reprecipitated with acid. This precipitate is 
heavy, flocculent, and amorphous, and, when heated above 40 to 50°C. 
in aqueous solution, turns to a black, tarry mass. On cooling and 
drying it is found to be brittle and may be broken into a fine, dry, 
almost black powder. The dry powder is soluble in acid ethyl alcohol 
and aqueous solutions of sodium, potassium, and ammonium hydrox- 
ids and carbonates. It is in part precipitated from acid alcohol by 
the addition of sodium carbonate, the portion precipitated being a 
sticky, black, tarry mass. Most of the iodin-containing compounds 
are soluble in alcohol in the presence of sodium carbonate, so that 
this is a valuable aid in the gross separation of the black, tarry impuri- 
ties from the constituents which contain iodin. However, some of 
the iodin is carried down by the sodium carbonate precipitation, 
sho\* ing that the iodin compound, although probably the same through- 
out all the different precipitates, is attached to various groups of com- 
pounds which possess different solubilities. 



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ISOLATION OF THE IODIN COMPOUND 399 

If barium hydroxid is added to the alcohol solution after removal 
of the sodium carbonate precipitate, practically all the rest of the 
dark-colored compounds are precipitated by the barium. This 
precipitate carries down varying percentages of iodin, depending on 
conditions. If the solution is made acid with hydrochloric acid 
before the addition of barium, a very high percentage of the iodin 
may be precipitated. If the solution is made alkaline with sodium 
hydroxid, a very small percentage may be carried down. Between 
these two limits the amount removed by the barium depends on the 
acidity and the temperature. Since the alcohol solution remaining 
after precipitation with barium is light straw-colored, the alcohol- 
barium-soluble constituents to which the iodin compound is attached 
are almost colorless. 

Similar separations may be produced in aqueous solution. If 
the dark brown alkaline solution of the hydrolyzed products is acidified, 
almost all the color and iodin compounds are precipitated. Barium, 
calcium, and magnesium salts, added to an alkaline aqueous solution 
of the acid-insoluble hydrolyzed constituents, precipitate practically 
all the dark-colored compounds, leaving a very light-colored solution. 
This precipitation divides the iodin present; about one-half is precipi- 
tated by the alkaline earths and one-half is soluble. 

These precipitation and solubility properties clearly show the nature 
of the material with which one has to work. It is a mixture of com- 
pounds in colloidal form, and the problem is not only one of separating 
a mechanical mixture. It was necessary to gain a clear insight into 
the chemical nature of the iodin compound and the other constituents 
before the separation of the two could be realized. 

The most striking property of the acid-insoluble group of hydro- 
lyzed products is their acidic nature. They may be dissolved in 
alkali and reprecipitated by acid without appreciable loss of iodin. 

Many attempts were made to separate the iodin compound by 
its solubility and precipitation properties with various reagents. 
No specific precipitant was found. No difference in solubility was 
found which could be used to effect a separation. After many attempts 
to separate the iodin compound had failed, it became apparent that 
the compound was not present in free form, but was still firmly bound 
to some unknown substances. 

Experiments showed that iodin was not broken off when dissolved 
in moderately strong sodium hydroxid. In the hope that heating 



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400 E. C. KENDALL 

in aqueous sodium hydroxid might produce a further hydrolysis, the 
acid-insoluble constituents of the alkaline-alcoholic hydrolysis were 
heated several hours in 5 per cent sodium hydroxid. It was then 
found that treatment with sodium hydroxid, followed by precipita- 
tion with an acid, will not effect a separation of the iodin compound 
from the black colloidal impurities. The solubility of the compounds 
present which do not contain iodin closely parallels the solubility of 
the iodin containing compound, and, as far as alkali and acid are con- 
cerned, no appreciable separation can be brought about by alternate 
treatment with each. 

Since the addition of a soluble barium salt to an alkaline solution 
of the acid-insoluble products of hydrolysis precipitates practically 
all the brown impurities and does not carry down all the iodin, this 
separation was invesligated to determine whether the percentage of 
iodin in the acid-insoluble constituents could thereby be increased. 
The acid-insoluble constituents were dissolved in dilute sodium hy- 
droxid, and barium hydroxid was added. The solution was heated in 
a nickel crucible at 100°C. for eighteen hours. This treatment pro- 
duced a precipitation of the brown compounds, giving a light vellow 
filtrate of the barium-soluble constituents. Determination of the iodin 
content of the filtrate showed that about 50 per cent of the iodin present 
had been precipitated from the alkaline solution by barium hydroxid, 
and 50 per cent remained soluble. Sodium sulfate was added to the 
water solution containing the barium-soluble constituents, and the 
barium was removed as sulfate. The solution was then acidified, 
and a copious precipitate obtained which still retained iodin. The 
precipitate was filtered off and dried. Analysis showed that the 
percentage of iodin had been very materially increased by this treat- 
ment. The iodin in the starting material amounted to about 5 per 
cent; after treatment with barium, as outlined above, and reprecipita- 
tion with an acid, the iodin was found to be about 15 per cent. 

The portion of the starting material which had formed a dark, 
flocculent precipitate with barium hydroxid was dissolved in sodium 
hydroxid and sodium sulfate. The barium sulfate was removed and 
the solution was acidified. A precipitate formed on the addition of 
the acid and when this was filtered off and dried it too was found to 
contain an increased percentage of iodin. By treatment with barium 
hydroxid the percentage of iodin contained in the hydrolyzed constit- 
uents of the thyroid proteins had been increased. 



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ISOLATION OF THE IODIN COMPOUND 401 

As this was the only material advance which had been made toward 
isolation of the iodin-containing compound, it was decided to investi- 
gate more fully the reactions involved between barium and the 
hydrolyzed products of the thyroid proteins. The two precipitates 
were dissolved in separate solutions of sodium hydroxid, barium 
hydroxid was added to each*, and the solutions were heated in nickel 
crucibles for eighteen hours at 100°C. The insoluble portions were 
filtered off, the barium was removed as outlined above, the barium 
soluble constituents of each crucible were combined and again acidified, 
the precipitate was filtered off and dried, and analysis showed that 
the percentage of iodin present had increased in the barium-soluble 
portion to 26 per cent. With many misgivings the precipitation with 
barium and heating in a nickel crucible were again repeated. The 
iodin content of the precipitate obtained was 33 per cent. Still 
another treatment yielded a product containing 42 per cent of iodin. 
The amount of material now consisted of less than 200 mg. The 
success of the method, however, called for still further treatment. 
It was carried out in the same manner, and a precipitate containing 
47.3 per cent of iodin was obtained. The character of the precipitate 
had changed and the color of the solution had almost disappeared. 
It seemed probable that some other method of purification could now 
be applied to the preparaton containing 47.3 per cent iodin. 

The material was dissolved in 95 per cent alcohol; solution was 
complete. The alcohol was evaporated on a water bath to a small 
volume, in the hope that some crystals might separate. By a chance, 
however, the dish containing the alcohol evaporated to dryness, and 
the dried precipitate was heated for about one hour after the alcohol 
had been driven off. It was thought that on the addition of more 
alcohol the white powder on the bottom of the dish would again be 
dissolved, and, possibly, crystals might still separate. More alcohol 
was therefore added, but a white incrustation on the bottom of the 
dish was insoluble in alcohol. I believed that this treatment had 
effected a further separation, that the iodin-containing compound was 
redissolved in the alcohol, and that the white incrustation represented 
impurities. It was filtered off. The weight of this white powder was 
18.6 mg. It was dissolved in sodium hydroxid, and a portion of it was 
used to determine iodin, when it was found that the iodin amounted 
to 60 per cent. The white incrustation was, therefore, not an im- 
purity, but the iodin compound itself. Its solubility in alcohol had 

'19—26 



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402 E. C. KENDALL 

been changed by heating the residue left after evaporation of the 
alcohol. More of the acid-insoluble constituents resulting from hydro- 
lysis of the thyroid proteins were treated in precisely the same manner, 
and about 200 mg. of the white residue were obtained. When this 
was dissolved in aqueous sodium hydroxid, precipitated by adding 
sulfuric acid and boiling, it was converted into fine white microscopic 
crystals. For reasons which will be given this iodin compound has 
been named "thyroxin," and it will be referred to by that name 
throughout the remainder of this article. 

As the yield of thyroxin depended on the amount of desiccated 
thyroid which could be treated at any one time, it was decided to 
enlarge our facilities for the hydrolysis of desiccated thyroid, which, 
up to this time, had been carried out in glass flasks. An eleven gallon 
galvanized iron tank was constructed, which could take care of 500 
gm. of desiccated thyroid at one time. The acid-insoluble constit- 
uents were obtained as before. They were dissolved in dilute sodium 
hydroxid, barium hydroxid was added, and the steps outlined above 
were carried out. No crystals of thyroxin were obtained. 

The work from this point will be presented in a logical rather than 
a chronological order, as many months were spent in elucidating 
the factors which prevented the isolation of more crystals. 

After working for fourteen months in an endeavor to repeat the first 
isolation of the crystals, it was found that there are five conditions 
which influence the isolation of thyroxin in pure crystalline form. 

1. Effect of temperature on precipitation with an acid. — When 
the partially purified, iodin-containing constituents are precipitated 
by an acid, the precipitate is flocculent and amorphous. If this is 
heated to from 40 to 50°C, it assumes a fine, granular form which can 
be filtered and washed very readily. This procedure was followed be- 
cause of the facility of handling the precipitate. Warming of the 
acid solution does not break off any iodin in inorganic form. If, 
however, this precipitate, which was prepared by warming the solution 
after the addition of the acid, is dissolved in alkali and heated with 
barium hydroxid, and the solution is again acidified, some iodin in the 
inorganic form may be found in the solution. If the precipitation by 
an acid is carried out in the cold, subsequent heating with barium hy- 
droxid and reprecipitation does not break off iodin in the inorganic form. * 

* Inorganic iodin has been tested for during this investigation by acidifying the 
solution with hydrochloric acid, adding starch and a few drops of sodium nitrite, 
producing a blue ring if inorganic iodin is present. 



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ISOLATION OF THE IODIN COMPOUND 403 

Since only one stage of this treatment could be carried out in 
one day, twenty-four hours intervened between the first acidification 
and warming of the solution and the second precipitation, after which 
iodin was demonstrated in the inorganic form in the filtrate. This 
time interval formed a convenient screen behind which the deleterious- 
action of heat remained hidden for many months. This influence of 
temperature on acidification was one of the most important causes for 
the failure to separate more crystals. Fearing that a concentrated 
sodium hydroxid solution would destroy the iodin compound, we had 
been neutralizing the alkali which was used to effect the primary 
hydrolysis with sulfuric acid before evaporating off the alcohol. As 
the amount of free alkali remaining in the alcohol was variable, de- 
pending on the amount of ammonia which had been evolved and the 
amount of water and carbonate in the alkali, it frequently happened 
that slight excess of acid was added, so that the alcohol was evaporated 
off in the presence of a small amount of acid. This we finally showed 
has a very destructive action on partially purified thyroxin. In this* 
connection it seems probable that the lack of physiologic activity of 
iodothyrin is explained by this action of acid on the iodin-containing 
compound. The iodin may not be broken off by treatment with 
acid, but the chemical properties, and undoubtedly the nucleus to 
which the iodin is attached, are altered so that the compound loses 
its physiologic activity. 

2. Effect of heating the alkaline hydrolysis solution in the presence 
of metal. — At first the hydrolysis was carried out in glass flasks. 
When an eleven gallon galvanized iron tank was substituted, the hydro- 
lysis was carried out apparently just the same, but it was found that 
with the metal the hydrolysis in an alkaline solution resulted in the 
breaking off of the iodin in the inorganic form. Investigation showed 
that in alkaline solution, iron, zinc, copper, tin, lead, German silver, 
and, in fact, all metals except nickel and the heavy metals, gold, silver, 
and platinum, break off iodin from its organic combination. A heavily 
enameled, cast iron kettle was found to give a satisfactory surface for a 
container in which to carry out the primary hydrolysis with sodium 
hydroxid in alcohol. Later this was replaced by a nickel kettle. 

3. Effect of carbon dioxid. — During the first separation of crystals 
carbon dioxid was neither employed directly nor was its effect excluded 
from the various steps in the process. After many months of failure 
to separate more of the iodin compound in crystalline form it was 



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404 E. C. KENDALL 

found that carbon dioxid plays an important role in the separation of 
thyroxin from the impurities. By chance an alkaline solution con- 
taining a partially purified preparation of thyroxin mixed with a large 
amount of impurities was precipitated with carbon dioxid instead 
of with sulfuric acid. The precipitate was filtered on a Buchner fun- 
nel and washed with distilled water. Instead of the distilled water 
running through lighter colored than the first filtrate, it was almost 
black (Fig. 197); Investigation showed that the black impurities 



.* 



u- 




Fig. 197. — Suction flask showing the color change which led to the investigation of the 
effect of carbon dioxid on the separation of thyroxin. 

were insoluble in water saturated with carbon dioxid but were soluble 
in distilled water. Even after the effect of the carbon dioxid on the 
separation of thyroxin was discovered, its explanation was, for many 
months, obscure. 

4. Effect of temperature during treatment of a solution with carbon 
dioxid. — After it was found that carbon dioxid had a very important 
action which allowed thyroxin to be isolated in crystalline form, carbon 
dioxid was added to the various solutions, first in the cold, and then 
it was added to the solutions- warmed to various temperatures up to 



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ISOLATION OF THE IODIN COMPOUND 405 

100°C. It was found that with the preparations which were contami- 
nated with a large amount of impurities, the passing of carbon dioxid 
into a solution above 50 to 60°C. resulted in breaking off iodin. This 
was confirmed many times, and, although for a long time unexplained, 
the solutions were always cooled before treatment with carbon dioxid. 

5. Effect of different samples of desiccated thyroid. — The fifth 
point is one beyond control, and was found to rest on the condition 
of the desiccated thyroid employed. The thyroxin content of different 
samples of desiccated thyroid varies as much as 400 per cent. It 
appears probable that bacterial or other decomposition so alters the 
proteins in some samples that it is impossible to separate any of the 
iodin compound. 

These five factors finally became apparent after a consideration 
of all the results obtained over a course of two years' investigation. 
It is remarkable that all these factors were unconsciously controlled 
during the first purification, especially as it took many months to find 
out that there were so many separate and distinct influences at work 
causing the destruction of the compound. 

The investigation of the chemical constituents of the thyrofd was 
begun by the writer in September, 1910. The use of barium salts 
to effect a separation was tried in November, 1914, and thyroxin was 
first [isolated in December, 1914. Although over 100 mg. were isolated 
at that time, it was not until February, 1916, that the effect of carbon 
dioxid was established and more of the substance was obtained. 
During the summer of 1916 several grams of thyroxin were separated, 
and by May, 1917, over 7 gm. were available for its chemical identifica- 
tion. The empirical and structural formulas were determined during 
the summer of 1917. In December, 1917, Mr. Osterberg succeeded 
in synthesizing a small amount of thyroxin. The synthesis was 
repeated and the structural formula confirmed in April, 1919. Up 
to the present time about 33 gm. of the compound have been separated 
from 6550 pounds of fresh thyroid material which has been made up 
almost entirely of hog thyroid (Fig. 198). The method may be briefly 
stated as follows: 

The fresh thyroid glands are hydrolyzed in 5 per cent sodium 
hydroxid. The fats are removed by rendering the sodium soap 
insoluble, and the clear alkaline filtrate is cooled and acidified. The 
acid-insoluble constituents containing practically 100 per cent of the 
thyroxin present are filtered off. This material is redissolved in 



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406 E. C. KENDALL 

sodium hydroxid and reprecipitated, using hydrochloric acid. The 
precipitate is now air-dried and is dissolved in 95 per cent alcohol. 
The excess hydrochloric acid which remains in the air-dried precipitate 
is neutralized with sodium hydroxid until it is almost neutral to 
moistened blue litmus paper. A heavy, black, tarry precipitate 
forms, which may be removed by filtration. The alcoholic filtrate 
is treated with barium hydroxid by adding a hot, very concentrated 




Fig. 198. — The three tanks in which 6550 pounds of hog thyroid glands were treated 
for the isolation of thyroxin. 

aqueous solution of the hydroxid to the alcohol, and refluxing. The 
treatment with barium removes some heavy dark impurities. A 
small amount of sodium hydroxid is added to the filtrate, and carbon 
dioxid is passed through the solution. The barium and sodium car- 
bonate are removed by filtration, and the alcohol is distilled. The 
last traces of alcohol are removed by heating in an evaporating dish. 
The aqueous residue is now acidified with hydrochloric acid. The 



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ISOLATION OF THE IODIN COMPOUND 407 

precipitate is dissolved in alkaline alcohol, carbon dioxid is passed 
through the solution, the precipitated sodium carbonate is removed, 
and the alcohol is evaporated. The last traces of alcohol are removed 
by heating on a water bath and the solution is allowed to stand. The 
monosodium salt of thyroxin will separate at this point. The yield 
is not quantitative, and it must be further purified by dissolving in 
alkaline alcohol, passing in carbon dioxid, distilling the alcohol, and 
allowing the monosodium salt to crystallize a second time. This 
may then be precipitated from an alkaline alcoholic solution by the 
addition of acetic acid. Resolution in alkaline alcohol and precipita- 
tion with acetic acid for five or six times removes the impurities and 
will yield thyroxin containing the theoretical percentage of iodin. 
A considerable percentage of the total iodin present is carried down 
in the neutral alcohol solution by the barium, and another portion is 
held in solution when the monosodium salt separates, but it is not 
practicable to try to separate the thyroxin from these precipitates, 
as the yield is very small. Physiologically they possess the same 
activity as thyroxin when administered according to the iodin 
content. 

After isolating about 7 gm. of thyroxin in the manner described, 
its empirical and structural formulas were determined and the sub- 
stance was shown to be 4, 5, 6 tri-hydro-4, 5, 6 tri-iodo, -2 oxy,-beta 
indolpropionic acid. Thyroxin exists in three forms: (1) the keto 
form with the carbonyl group adjacent to the imino, (2) a tautomeric 

I r H 

,h/ ( \ h h y > 

I I ' H H \ 0H 

H 1 I ! 

ir c c-o 

H 

H 

enol form of this with an alpha hydroxy group and double-bonded 

nitrogen with no hydrogen attached to the imino, and (3) a form in 

,H/ C \ H H /> 

l v c - c—r—c—cf 

I I H H \()H 

H ' ' 

,C (' C— OH 



\ r y\ N / 



H 



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408 E. C. KENDALL 

which there is an open-ring structure, the elements of water entering 
between the imino and the carbonyl with the formation of an amino 
and a carboxyl group. A consideration of the isolation of thyroxin 
after its structural formula had been determined explains the chemical 
reactions involved in the purification and isolation of the substance. 

A CONSIDERATION OF THE REACTIONS INVOLVED IN THE ISOLATION OP 

THYROXIN 

Thyroxin was first separated by following a method of treatment 
which was found to increase progressively its iodin content, and 
for the isolation of much of the material so far prepared this same 
method was followed without any light being thrown on the exact 
nature of the chemical reactions involved. The use of barium salts 
for the separation of thyroxin was first tried because of their ability 
to precipitate the dark-colored impurities from an alkaline solution 
of the hydrolyzed thyroid proteins. With the solutions of hydrolyzed 
proteins at first used, about 50 per cent of the total iodin could be 
precipitated by barium hydroxid. When the barium-soluble con- 
stituents were precipitated by an acid and redissolved in sodium 
hydroxid or carbonate, barium salts were found to precipitate some 
of the compounds which had previously been soluble in the presence of 
barium. This in time led to the discovery that the solubility of 
thyroxin in the presence of barium hydroxid was a test of its purity. 

Partially purified thyroxin which is soluble in barium hydroxid is 
also soluble in sodium carbonate and in alcohol. Pure thyroxin is in- 
soluble in these reagents. The process of purification rested essentially 
on the repeated treatments of the impure preparations of thyroxin 
with barium hydroxid and the recovery of the barium-soluble com- 
pounds by precipitation with an acid. The barium-insoluble constitu- 
ents were recovered as sodium salts after decomposition with sodium 
sulfate and then precipitated with an acid. 

After six or eight such barium treatments it was found that an 
increasing percentage of the total iodin was insoluble in barium 
hydroxid and finally it was shown that thyroxin could not be 
separated in crystal form from alcohol so long as it was soluble in 
barium hydroxid. Treatment with barium hydroxid influenced 
the separation of thyroxin in four different ways: (1) it effected a 
separation between the two forms of thyroxin, one barium-soluble, 



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ISOLATION OF THE IODIN COMPOUND 409 

the other barium-insoluble; (2) it caused the destruction of certain 
of the impurities which were present; (3) it precipitated certain 
impurities from the solution thereby effecting a separation; and (4) 
it carried down mechanically, when it was precipitated as barium 
sulfate, the dark-colored colloidal impurities which had almost identical 
solubilities as thyroxin itself and which were not removed by any 
other means. 

The chain of events which led to the explanation of the reactions 
involved in the separation of thyroxin from the other compounds 
contained in the acid-insoluble products of the alkaline hydrolysis 
and the conversion of barium-soluble thyroxin into barium-insoluble 
thyroxin was as follows: 

It was found that derivatives attached to the imino group render 
thyroxin soluble in alcohol. This was found true of the acetyl, the 
formyl, the ureide, the sulfate, and the hydrochlorid. It was also 
found that derivatives attached to the imino group do not form crystal- 
line di-silver salts. 

When thyroxin is partially purified, so that it contains from 30 
to 50 per cent of iodin, it is soluble in alcohol and it does not form a 
crystalline silver salt. These reactions suggested that the difficulty 
in purification arose from the fact that some derivative was attached 
to the imino group, which rendered the compound soluble in alcohol 
and prevented its precipitation with silver. Since it had already been 
found that the sodium salts of the acetyl, the formyl, and other deriva- 
tives of the imino were readily thrown out of solution in crystalline 
form by increasing the amount of sodium hydroxid present, attempts 
were made to determine the group attached to the imino in partially 
purified thyroxin by precipitating its sodium salt with a high concen- 
tration of sodium hydroxid. Partially purified barium-soluble 
thyroxin containing about 40 per cent of iodin was therefore dissolved 
in sodium hydroxid, and a solution of 30 per cent sodium hydroxid 
was added to this. As had been hoped, the addition of the stronger 
alkali soon produced a cloudy precipitate which did not settle but 
remained suspended, due to the high specific gravity of the solution. 
This was centrifugalized, the supernatant liquid contained most of 
the yellow impurities, and the precipitate remained as a firm felt on 
the bottom of the tube. It was dissolved in distilled water, sodium 
hydroxid was again added, the precipitate again formed, but this 
time it separated in more distinct particles and the solution was less 



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410 E. C. KENDALL 

turbid. It was centrifugalized, the supernatant liquid was still yellow, 
but showed much less color than the first solution. The residue 
in the bottom of the tube was again dissolved in distilled water, 
sodium hydroxid was added, and this time the precipitate assumed a 
still different form, coming down in distinct separate particles, practi- 
cally white, and the solution was almost colorless. These particles 
were examined under the microscope. They were the typical disodium 
salt of pure thyroxin itself, and not of a derivative. They were centrif- 
ugalized from the alkali, dissolved in alcohol, and precipitated by the 
addition of acetic acid, when they were recovered as pure crystalline 
thyroxin. 

The substitution of sodium chlorid for sodium hydroxid per- 
mitted the solutions to be filtered instead of centrifugalized, and 
it was then found that sodium chlorid precipitated the disodium 
salt of thyroxin from an alkaline solution even better than sodium 
hydroxid. Although this sample of thyroxin had been completely 
soluble in barium hydroxid, it was now insoluble in such a solution. 
As this change in solubility could not have been brought about by 
the hydrolysis of a derivative attached to the imino group, it was 
apparent that solubility in barium hydroxid depends on the presence 
of certain impurities. 

Investigation of the impurities which were separated from thyroxin 
by salting out the crystals from the alkaline solution showed that 
they are soluble in ether, that they are acidic in nature, and contain 
indole derivatives which give the pine-splinter reaction after fusion in 
caustic alkali. If pure crystalline thyroxin is dissolved in dilute 
sodium hydroxid and some of these indole derivatives are added to 
the solution, there appears to be an immediate reaction between 
thyroxin and these impurities which completely alters the chemical 
properties of thyroxin. The presence of these impurities renders 
thyroxin soluble in barium hydroxid, and instead of separating with 
sodium chlorid as the crystalline disodium salt, it is thrown out of 
solution as an oily tar. 

Since it was shown .that this great alteration in the chemical 
properties of thyroxin could be brought about by the presence of 
certain indole derivatives of acidic nature, and since the change 
was not due to the hydrolysis of a derivative attached to the imino 
group, the first explanation was that the imino group was rendered 
more reactive by the presence of the impurities and that a salt forma- 



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ISOLATION OF THE IODIN COMPOUND 411 

tion occurred similar to the sulfate or hydrochloric!, the acidic group 

being attached to the imino nitrogen. However, it was difficult to 

explain all the reactions by such a change. 

The first proof of the chemical reactions involved was obtained 

after preparation and analysis of the acetyl derivative. In the 

acetyl derivative of thyroxin, only one acid group is left which can 

react with a metal; therefore, a mono-metal derivative should be 

I r H 
!H/ l \ H H y> 

i H H \oh 

"c C C=0 



\c/\n/ 



H | 

1 



obtained. Analysis of the silver salt of the acetyl showed that 
apparently two atoms of silver had added to the acetyl. The simplest 
explanation for this would be the opening of the pyrrole ring between 
the imino and carbonyl groups with the formation of the second free 
I„H 



,H/ C \ H H y> 

I I H H \ H 



H 



jC C O=0 



H /\ 
H H 



O 
H 



carboxyl group. Further investigations showed that this is most 
probably true and that a similar opening of the ring occurs in thyroxin. 
The relation between the two forms is precisely the same as the rela- 
tion between creatinin and creatin. The opening of the ring in- 
creases the acidic properties of thyroxin and renders it soluble in 
sodium carbonate, barium hydroxid, and alcohol. It prevents 
the formation of a crystalline insoluble di-silver salt and, in fact, 
all the changed properties of thyroxin are adequately explained by 
this reaction. 

Analysis shows that the iodin content of barium-soluble thyroxin 
may be as high as 58 or even 60 per cent. This iodin content excludes 



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412 E. C. KENDALL 

the possibility of any group being attached to the imino, having a 
higher molecular weight than formic acid. Furthermore, barium- 
soluble thyroxin can be changed and separated in pure crystalline 
form, insoluble in barium hydroxid, merely by allowing an aqueous 
sodium carbonate solution to stand several weeks. Under these 
conditions there is a slow closing of the ring with the formation of 
the mono-salt which is only slightly soluble. It seems most 
probable that the impurities present do not react in a stoichiometric 
relation with all the thyroxin, but that the presence of even 
a small percentage of the impurities introduces the factor of time and 
greatly delays the rate at which the ring closes. 

Sufficient proof that a group is not attached to the imino group 
of partially purified thyroxin which is soluble in barium hydroxid, 
alcohol, and sodium carbonate is furnished by the fact that it is 
impossible to hydrolyze the acetyl from the imino group without 
disruption of the molecule. This also applies to all derivatives so 
far studied in which a group is attached to the nitrogen. Hydrolysis 
does not remove the group but destroys the integrity of the molecule. 
Therefore, the reactions occurring during purification cannot be the 
removal of a group attached to the imino. In the body it appears 
probable that thyroxin exists in the open-ring form with an amino 
and two carboxyl groups. The problem then in isolation is to estab- 
lish conditions favorable for the closing of the pyrrole ring. The 
open-ring form of thyroxin will not crystallize and although it is but 
slightly soluble in acid, its solubility in carbonates, barium and calcium 
hydroxid, alcohol, and pyridin are in striking contrast to the closed- 
ring form which is insoluble in all these reagents. In the presence 
of certain impurities it appears very difficult, sometimes impossible, 
to close the ring and thereby separate thyroxin. The mere presence 
of these impurities is sufficient to open the ring if pure crystalline 
thyroxin is added to a solution of such impurities. 

The exact nature of these impurities is still unknown, but they 
are among the hydrolyzed products of the thyroid proteins and 
contain the indole nucleus. Animo-acids from gelatin do not cause 
thyroxin to exist in the open-ring form. The difficulties encountered 
in separating the closed-ring form of thyroxin from any solution 
depends on the ratio between the amount of thyroxin present and the 
amount of impurities present. Thyroxin appears to carry down either 
chemically or mechanically these impurities so that solution in alkali 



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ISOLATION OF THE IODIN COMPOUND 413 

and precipitation with acid do not effect a separation. The best 
conditions so far found for the closing of the ring and the separation 
of thyroxin are obtained by solution of thyroxin in sodium carbonate. 
Under these conditions the ring slowly closes and the monosodium 
salt, which is only slightly soluble, deposits in crystalline form on the 
bottom of the flask. 

SUMMARY 

The chemical reactions involved in the five conditions, which 
influence the isolation of thyroxin, may be summarized as follows: 

1. Effect of temperature on precipitation with an acid. — The 
chemical reactions involved in the acidification with an acid were very 
obscure until the acetyl derivative was prepared. It was found that 
when an acid suspension of the acetyl is neutralized with sodium 
hydroxid, at the neutral point, iodin breaks off from the acetyl 
derivative, and the liberation of iodin may be shown to be a matter 
of oxidation and reduction. Thyroxin is far less susceptible, and an 
acid suspension of thyroxin may be neutralized with an alkali without 
any such liberation of iodin occurring. When, however, an impure 
preparation of thyroxin is neutralized, the impurities appear to in- 
fluence thyroxin in a manner similar to the addition of the acetyl 
group to the molecule, and at the proper hydrogen ion concentration, 
which is very nearly the neutral point, there is a reaction between the 
impurities and thyroxin resulting in a breaking off of iodin. Tem- 
perature greatly influences this reaction. If carried out in the cold 
solution, no destruction of thyroxin occurs. 

Another effect of temperature during acidification is probably that 
of polymerization. Indole compounds polymerize very readily in 
the presence of acid. Thyroxin in pure state is slowly changed by 
boiling in strong acid, but when only partially purified the action of 
strong acid and heat brings about such a deep-seated alteration in the 
molecule that its physiologic activity is destroyed. 

2. Effect of heating the alkaline hydrolysis solution in the presence 
of metal. — Thyroxin is very susceptible to reduction. An alkaline 
solution of thyroxin may be completely decomposed by heating with 
metallic zinc; the iodin is broken off from the molecule. Without 
doubt, the other metals, iron, copper, tin, lead, German silver, and, 
in fact, all metals except nickel, gold, silver, and platinum, react in 
the same manner, causing the destruction of thyroxin by reduction. 



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414 E. C. KENDALL 

3. Effect of carbon dioxid. — There are two distinct actions pro- 
duced by carbon dioxid. One is partial purification of thyroxin 
by precipitation from an alkaline solution. If an alkaline solution of 
partially purified thyroxin is treated with carbon dioxid until no 
further precipitation is produced, and the precipitate is removed by 
filtration, a large amount of material may be precipitated in the 
filtrate by the addition of a stronger acid. Thyroxin is precipitated 
by carbon dioxid more completely than, and at a point far in advance 
of, certain of the impurities. The effect of carbon dioxid as a pre- 
cipitant depends on the ratio between the amount of thyroxin and the 
amount of impurities present. In the first solution of the acid-in- 
soluble constituents of the hydrolyzed thyroid proteins, carbon dioxid 
will not precipitate any thyroxin. As the impurities are removed, the 
precipitation of thyroxin by carbon dioxid becomes more and more 
complete until in a solution of pure thyroxin the precipitation with car- 
bon dioxid is quantitative. This influence of the impurities on the pre- 
cipitation of thyroxin by carbon dioxid is one of the most striking ex- 
amples of the effect of impurities on the chemical properties of thyroxin. 

Another influence of carbon dioxid on the separation of thyroxin 
is more deep seated and was, at first, very difficult to explain. Thy- 
roxin is soluble in sodium hydroxid with the formation of the disodium 
salt. If carbon dioxid is passed into such a solution, the hydroxy 
group gives up its sodium and exists in the free form. The carboxyl 
group, however, retains the sodium in the form of a mono-metal 
derivative. This is far less soluble than the di-metal derivative and 
readily crystallizes from the solution. When partially purified 
thyroxin, which exists in the open-ring form, i* treated in this manner 
with sodium hydroxid and carbon dioxid, the optimum conditions 
are produced for the closing of the ring, and after standing for a con- 
siderable length of time the ring closes w T ith the crystallization of the 
mono-metal salt of the closed-ring form of thyroxin. 

4. Effect of temperature during the treatment of a solution with 
carbon dioxid. — This is closely related to, and is probably identical 
with, the effect of temperature on acidification of a solution with a 
mineral acid. The effect is the breaking off of iodin from the thyroxin 
molecule, and the mechanism is undoubtedly a reduction due to the 
presence of impurities and accelerated by the increase in temperature, 
the carbon dioxid functioning merely in producing the proper hydro- 
gen ion concentration for this reaction to take place. 



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ISOLATION OF THE IODIN COMPOUND 415 

5. Effect of different samples of desiccated thyroid. — One of the 
most important reasons for the failure to separate thyroxin con- 
sistently was the variability of the samples of desiccated thyroid used. 
Analysis of the samples obtained at different times of the year shows 
that in the winter months, January, February, and March, the iodin 
content of the glands may be so low as to make the isolation 
impracticable. During the summer months the thyroxin content of 
the gland increases from 400 to 500 per cent and allows a much more 
liberal and much simpler purification of thyroxin. The amount of 
impurities present appears to be more nearly constant, so that in the 
winter months the problem is greatly complicated by having to deal 
with approximately the same amount of impurities and with a greatly 
diminished amount of thyroxin. It is significant that the real progress 
was made with the problem only when a satisfactory sample of desic- 
cated thyroid was obtained, but this was demonstrated only after the 
completion of the work. Another influence, which undoubtedly is 
very important, not only in the isolation of the substance but in the 
consideration of the therapeutic value of any sample of desiccated 
thyroid, is the state of preservation of the thyroid proteins. Thyroxin 
has been shown to contain two carboxyl groups and one amino group, 
when existing in open-ring form, in which state it undoubtedly does 
exist in the thyroid proteins. Deamination and decarboxylation by 
bacteria are well known, and it seems highly probable that some 
samples of desiccated thyroid are without therapeutic value because 
of bacterial decomposition. Bacterial action could very readily 
result in deamination and decarboxylation of thyroxin, which would 
render the substance without physiologic activity although the iodin 
content of the material would not be altered. 

BIBLIOGRAPHY 

1. Baumann, E.: Ueber das normale Vorkommen von Jod im Thierkorper. Ztschr. 
f. physiol. Chem., 1895-1896, xxi, 319-330. 

2. Baumann, E.: Ueber das normale Vorkommen des Jod im Thierkorper. Ztschr. 
f. physiol. Chem., 1896-1897, xxii, 1-17. 

3. Hunt, R. and Seidell, A.: Studies on thyroid. I. The relation of iodin to the 
physiological activity of thyroid preparations. Bull. Hyg. Lab., U. S. P. H., 1908, No. 47. 

4. Kendall, E. C: Studies in the chemistry and physiology of the thyroid. I. The 
determination of iodin in the thyroid. Jour. Biol. Chem., 1914, xix, 251-256, also, Col- 
lected Papers of the Mayo Clinic, 1914, vi, 346-351; II. A method for the decomposition 
of the proteins of the thyroid, with a description of certain constituents. Jour. Biol. 
Chem., 1915, xx, 501-509, also, Collected Papers of the Mayo Clinic, 1914, vi, 352-362. 



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416 E. C. KENDALL 

5. Kendall, £. C: The isolation in crystalline form of the compound containing 
iodin which occurs in the thyroid; its chemical nature and physiologic activity. Tr. 
Assn. Am. Phys., 1915, xxx, 420-449, also, Collected Papers of the Mayo Clinic, 1915, 
vii, 393-421. 

6. Kendall £. C: The active constituent of the thyroid; its isolation, chemical 
nature, and physiologic action. Collected Papers of the Mayo Clinic, 1916, viii, 513- 
527. 

7. Kendall, E. C: The thyroid hormone. Collected Papers of the Mayo Clinic, 
1917, ix, 309-336. 

8. Oswald, A.: Zur Kenntniss des Thyreoglobulins. Ztschr. f. physiol. Chem., 
1901, xxxii, 121-141. 

9. Pick, £. P. and Pineles, F.: Untersuchungen Uber die physiol ogisch wirksame 
Substanz der Schilddrllse. Ztschr. f. exper. Path. u. Therap., 1909-1910, vii, 518-531. 

10. Vaughan, V. C, Vaughan, V. C, Jr. and Vaughan, J. W.: Protein split products 
in relation to immunity and disease. Philadelphia, Lea and Febiger, 1913, 476 pp. 



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THE PHYSIOLOGIC ACTION OF THYROXIN* 

E. C. KENDALL 

In 1914 the physiologic action of the iodin compound occurring in 
the thyroid was in part described. 2 At this time it was stated that 
after the administration of this substance to dogs there was in every 
case a long delay before any physiologic effects were demonstrable. 
The action was described as follows : 

"When injected subcutaneously in animals, there is at first no 
effect on either the pulse rate or the blood pressure. After from 
twenty-four to thirty-six hours the dog appears restless, has a slight 
increase in temperature, and a decided increase in pulse rate. If a 
series of injections is given on successive days, these symptoms are 
aggravated, and after two or three injections they are accompanied by 
a distinct tremor, loss of weight, and severe diarrhea. On the fourth 
or fifth day of injection the pulse rate is between 200 and 300, and all 
the other symptoms continue with increased severity." 

While the investigation concerning the physiologic action of 
thyroxin is not yet completed, certain progress has been made which 
will be reported at this time. The iodin compound which in 1914 was 
tentatively named the " alpha iodin " compound, in order to differen- 
tiate it from the other iodin compounds occurring in the gland which 
were called "beta," has now been given the name "thyroxin." 

Further investigation has confirmed the delay in the action of 
thyroxin in animals and in man, both in the normal condition and 
in myxedema. In a long series of patients suffering from myxedema 
who have been treated by intravenous injection of known amounts of 
thyroxin, Plummer has found that in all except two there was a 
very marked delay in the action of thyroxin. In these two patients 
there was a short-lived immediate response, but the prolonged action 
of thyroxin was noted as usual and the curve of the response 
after the first few hours was approximately the same as that given 
by the other patients. 

* Reprinted from Endocrinology, 1919, iii, 156-163. 
•1&-27 417 



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418 E. C. KENDALL 

Some of the early observations on the delayed action of thyroxin 
were obtained on goats. A series of eleven goats was injected daily 
with 14 mg. of thyroxin. The first goat died after eleven days and the 
rest followed at short intervals, all dying within thirty days. This 
shows that the long-continued presence of thyroxin in the animal 
organism is incompatible with life and it also suggests that death is 
not caused from the toxic action of the substance itself, but from 
secondary reactions. In order to bring this out more clearly another 
normal goat was injected with 230 mg. of thyroxin in a single injec- 
tion. This amount was one and one-half times as much as was re- 
quired to kill the first goat of the series, and yet the single injection 
of this relatively enormous dose produced almost no demonstrable 
effect, and the goat, even from the second day after the injection was, 
to all intents, normal. 

Massive doses of thyroxin have also been given to dogs. Some 
were injected with thyroxin while they were receiving intravenous 
injections of sugar or of amino acids. In a few of these animals it 
was possible to demonstrate an immediate response to thyroxin, but 
this response very rapidly subsided and a long delay period followed 
before there were definite signs of the functioning of thyroxin. 

Since the successive daily administration of thyroxin brings about 
death, and a single injection of enormous doses produces, in most 
instances, no demonstrable effect, we may conclude that the thyroxin 
molecule per se is not toxic to the animal organism. Although the 
intravenous injection of thyroxin produces no change in blood pressure, 
pulse rate, nervous manifestations, or any of the so-called hyperthy- 
roid symptoms, the long-continued presence of thyroxin within the 
tissues of the body produces the picture of hyperthyroidism in its 
entirety, terminating in great emaciation and eventually in death. 
One factor, therefore, which would determine the reactivity of thy- 
roxin would be the speed with which the tissues absorb thyroxin 
from the blood-stream. Even though thyroxin is circulated through 
the tissues of the body in the blood-stream, if the tissues refuse to 
absorb it from the blood it obviously could not produce its normal 
physiologic action. In order to determine whether or not the tissues 
remove thyroxin from the blood, 200 mg. were injected at once into 
the saphenous vein of a dog, and the bile and urine were saved for the 
next fifty hours. The bile and urine were analyzed for iodin and it was 
found that 43 per cent of the total iodin contained in the thyroxin 



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THE PHYSIOLOGIC ACTION OF THYROXIN 419 

injected was excreted in the bile within fifty hours, and 13 per cent 
was excreted in the urine during the same time. This accounts for a 
large amount injected and, while the thyroid gland of this animal was 
not analyzed for iodin, it is highly probable that the remaining amount 
injected was removed from the blood-stream by the thyroid gland and 
there retained, making practically 100 per cent of the injected thyroxin 
unavailable for functioning within the tissues. 

Marine and others have shown that the thyroid absorbs iodin 
when present in the blood and there can be little doubt that the gland 
absorbs and holds thyroxin, so that between the liver, the kidneys, 
and the thyroid gland, the excess of thyroxin is adequately cared for, 
and the tissues from a single injection do not take up enough thyroxin 
to result in a demonstrable physiologic response. 

While no demonstrable physiologic response follows a single 
injection of thyroxin, there is no doubt that there is a physiologic 
response even to very small amounts. By the determination of the 
basal metabolic rate it may be shown that the myxedematous patient 
responds to exceedingly small amounts of thyroxin given in single 
injections. By "demonstrable response" is meant the increase in 
pulse rate and nervous manifestations with loss of weight, such as 
are observed when several administrations of thyroxin are given. 
The difference in the condition in the dog after one injection of thyroxin 
and after five injections is very striking, even though the weight of 
thyroxin given in the single injection is as great as the total amount 
used in the five injections. 

Since the absence of thyroxin from the organism results in a 
lowered level of metabolic rate, and the administration of thyroxin 
determines the basal metabolic rate in the myxedematous patient, 
it seems highly probable that under normal conditions an equilibrium 
exists between the thyroxin in the thyroid gland, the amount in the 
blood-stream, and the amount in the tissues. It is probable that the 
amount in the tissues fluctuates according to the energy demands of 
the body, but that there is always an equilibrium seems highly prob- 
able. Under these conditions, if a large amount of thyroxin is 
injected into the blood-stream and nothing is done calling for an in- 
creased thyroxin content of the tissues, the tissues apparently are 
unable to absorb more thyroxin than their normal content and the 
excess is treated as a foreign substance and is promptly excreted in 
the bile. Some portion, however, is either excreted unchanged in the 



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420 E. C. KENDALL 

urine or is broken down and thus excreted. If thyroxin is injected 
on several successive days the amount in the thyroid gland, the 
amount in the liver, and the amount in the blood eventually pass 
the normal limits for an appreciable period of time, with the result 
that the tissues are forced to absorb more than their normal content 
of thyroxin. When this process has started and secondary effects are 
brought into play the tissues are stimulated to such a height of 
activity that they, themselves, demand more thyroxin, and so the 
physiologic response is slowly built up. The full effect of the step- 
ping-up process, however, is a matter of days, not a few hours. The 
tissues, once they have absorbed the thyroxin and begin to function 
at a higher rate of activity, in turn may affect the other ductless 
glands, especially the adrenal, as suggested by Cannon, and the in- 
creased activity of the adrenal, in turn, produces its train of effects. 
Quantitative studies of thyroxin by Hummer have shown that not* 
only is the appearance of physiologic effects of thyroxin delayed in 
man, but the duration of the effects is surprisingly long, and the 
maximum effect from a single injection of thyroxin in myxedematous 
patients is not reached until the tenth day. After reaching the maxi- 
mum effect, thyroxin still continues to function for another eight to 
ten days, so that the length of time a single administration of thy rox in 
functions within the body is about three weeks. 

What chemical reactions are so stimulated by thyroxin that life 
is incompatible are still unknown; but it is obvious that death is not 
due, in a strict sense, to the presence of thyroxin itself, but is due to 
the secondary effects which thyroxin brings into play. 

One of the most important findings in connection with the physio- 
logic activity of thyroxin has been the establishing of the quantitative 
relation between thyroxin and the basal metabolic rate. Plummer 
has shown that 1 mg. of thyroxin in an adult weighing approximately 
150 pounds increases the metabolic rate 2 per cent. The curve of 
this response has been shown to be approximately a straight line 
between metabolic rates 80 per cent below normal to from 15 to 20 
per cent above normal. This finding, coupled with the observation 
that all myxedematous patients tend to approach a uniform metabolic 
rate, which is about 40 per cent below normal, is extremely strong 
evidence in favoi of the hypothesis that without the presence of thy- 
roxin within the animal organism, rapid and large fluctuations in energy 
output would be impossible. Clinically this is substantiated by the 



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THE PHYSIOLOGIC ACTION OF THYROXIN 421 

great difficulty the myxedematous patient manifests when endeavor- 
ing to walk upstairs or carry out any other muscular activity. Their 
range of fluctuation of energy output is limited. Their normal 
existence is at a rate in the neighborhood of 40 per cent below normal. 
However, by the administration of thyroxin this basal metabolic rate 
can be raised to any desired figure, and it can be so maintained over 
periods of time measured in years. These facts suggest that in the 
normal animal organism thyroxin is not fundamentally essential to 
life. The fundamental chemical reactions occur.and life is maintained 
in the complete absence of thyroxin, but in this condition the flexibility 
of energy output is limited to a narrow range. The addition of the 
thyroid apparatus to the animal organism establishes not only a 
higher plane of basal energy output, but it supplies the mechanism 
which permits the maximum range in flexibility of energy output. 
The amount of thyroxin within the tissues is undoubtedly a physiologic 
constant, a figure as constant per weight of tissue as the normal 
number of red cells per cubic millimeter of blood. What determines 
this normal content of thyroxin is unknown. What maintains the 
content of thyroxin within the tissues is obviously the blood-stream. 
Some work has already been completed in this laboratory which has 
the objective of determining the thyroxin content of the blood and 
tissues. This may be done by determining the maximum iodin content 
of the blood and tissues. Whether or not the total iodin in the blood 
and tissues is 100 per cent in the form of thyroxin or 50 per cent 
cannot be shown, but the total amount of thyroxin could not be more 
than the amount indicated by the total iodin present in the tissues. 
The method for the determination of iodin which was published by 
the writer in 1914 has recently been further refined and perfected so 
that now one part of iodin in ten to twenty millions can be determined 
with a high degree of accuracy. By the use of this method it has been 
shown that the iodin content of the blood of animals is approximately 
1.5 to 2 parts per ten millions; that is, 15 to 20 one-thousandths of 
1 mg. per 100 c.c. The iodin content of the tissues is slightly higher, 
averaging 2.5 to 3 parts per ten millions; and the content of the liver 
is still a little higher, from 3.5 to 4 parts per ten millions. These 
figures must be amplified and confirmed by still more work, which 
is now being carried out, but they already indicate that there is aa 
equilibrium existing between the amount of thyroxin in the blood, 
in the tissues, and in the liver. 



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422 E. C. KENDALL 

If the presence of thyroxin within the tissues determines the meta- 
bolic activity of the tissues it is obvious that if there were no mechanism 
for varying the amount of thyroxin and if the tissues always contained 
enough thyroxin to permit of their maximum output of energy, the 
control of the energy output during periods of rest would be, to say 
the least, difficult. Whether or not the thyroxin content of the tissues 
diminishes after a period of great exertion, the thyroxin being carried 
back to the thyroid gland by means of the blood-stream and there 
held as a reservoir until further demanded, is still unknown. 

This, mechanism is at least indicated and is in part substantiated 
by the findings of the seasonal variation of the iodin in the thyroid 
gland. Seidell and Fenger have shown that during the winter months 
the thyroid glands of beef, sheep, and hogs all contain much less iodin 
than during the summer months. It is apparent that during the 
winter months more energy is required to maintain body temperature, 
and the low iodin content of the gland could be explained either by 
the fact that the thyroid gland has given up its supply of thyroxin 
to the tissues or by an actual wearing out of thyroxin due to the 
prolonged functioning of the substance in the tissues, so that during 
January, February, and March the amount left in the gland would 
be at a minimum. During the summer months, with less energy 
production in the animal, the amount of thyroxin demanded in the 
tissues is less. It reappears in the gland, either because its rate of 
production is greater than its rate of destruction, or because the amount 
in the tissues is returned to the gland and held there for use at some 
future time. The seasonal fluctuation of thyroxin in the gland is more 
satisfactorily explained on this basis than on the basis of varying 
iodin content of the food, and as it holds for beef, sheep, and hogs, it 
is suggestive that the mechanism of the variation is essentially due 
to the varied energy output of the animals during the cold and the 
hot months of the year. 

In conclusion, the physiologic action of thyroxin is probably that 
of a catalyst which bears a quantitative relation to the production 
of energy within the tissues, and the curve representing this relation 
is a straight line; that is, the increase in energy production with an 
increasing amount of thyroxin is simply an additive one. The sub- 
stance appears to function within the tissues, and there is an 
equilibrium between the amount in the tissues, the amount in the 
bloodstream, and its source of supply, the thyroid gland. The entire 



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THE PHYSIOLOGIC ACTION OF THYROXIN 423 

absence of the substance from the body does not produce death, but 
merely a lowering of the level at which energy can be produced by the 
animal organism. In administering more than the normal amount 
of thyroxin to the animal organism there is a distinct lag in the absorp- 
tion of the compound by the tissues and there is a rapid return to the 
normal content if the administration of the substance is stopped/ 
The chemical reactions which are brought into play by the administra- 
tion of thyroxin are probably not different from the fundamental 
chemical reactions occurring in its absence. As a catalyst it merely 
increases the rate at which these fundamental reactions are carried 
out. The thyroid apparatus apparently has been added to the animal 
organism in order to permit a greater range of flexibility of energy 
output than would exist without such a mechanism. 

BIBLIOGRAPHY 

1. Cannon, W. B., Binger, C. A. L. and Fitz, R.: Experimental hyperthyroidism. 
Am. Jour. Physiol., 1914-1915, xxxvi, 363-364. 

2. Kendall, £. C. : The determination of iodin in connection with studies in thyroid 
activity. Jour. Biol; Chem., 1914, xix, 251-256. A method of decomposition of the 
proteins of the thyroid, with a description of certain constituents. Jour. Biol. Chem., 
1915, xx, 501-509. 

3 Marine, D. and Rogoff, J. M. : The absorption of potassium iodid by the thyroid 
gland in vivo, following its intravenous injection in constant amounts. Jour. Phar- 
macol, and Exper. Therap., 1916, viii, 439-444. 

4. Plummer, H. S.: Personal communication. 

5. Seidell, A. and Fenger, F. : Seasonal variation in the iodin content of the thyroid 
gland. Jour. Biol. Chem., 1912-1913, xviii, 517-526. 

Fenger, F.: On the seasonal variation in the iodin content of the thyroid gland. 
Endocrinology, 1918, ii, 98-100. 



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THE CHEMICAL IDENTIFICATION OF THYROXIN 

Second Paper* 

E. C. KENDALL AND A. E. OSTERBERG 

Thyroxin is a white, highly crystalline substance, odorless, and 
tasteless. It may be separated from aqueous or alcoholic solutions 
in microscopic crystals which are not soluble in any organic solvent, 
except those which are strongly basic or acidic in nature. It is soluble 
in alcohol in the presence of mineral acid or an alkali metal hydroxid. 
It is stable toward heat, and its melting point is in the neighborhood 
of 250°C. Since it is odorless and colorless and is not easily affected by 
oxidation and reduction, its most important chemical and physical 
properties are concerned with the acidic and basic groups within the 
molecule. Thyroxin is a weak acid, but possesses basic properties in 
the presence of mineral acids. 

In 1915, it was suggested that the organic nucleus in thyroxin is 
indol (2). Its solubility in alkali metal hydfoxids, but not in carbo- 
nates, indicated that it was of phenolic nature, and its salt-forming 
power with acids was attributed to an imino group. After it was 
known that thyroxin contained about 60 per cent of iodin, and before 
the empiiical and structural formulas were determined, the chemical 
properties of the molecule were best expressed by di-iodo-di-hydroxy- 
indol. 

The first derivative of thyroxin, which helped to give an insight 
into its chemical structure, was the sulfate. Thyroxin which was 
precipitated from alkaline alcohol by acetic acid was found to contain 
65 per cent of iodin. Thyroxin, precipitated by boiling an aqueous 
ammoniacal solution, also contained 65 per cent of iodin. Thyioxin, 

* Reprinted from Jour. Biol, (hem., 1919, xL 263-334. 

424 



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THE CHEMICAL IDENTIFICATION OF THYROXIN 



425 




*«. 199.- 



-The hydrochloric! of thyroxin which separates in flat plates, rectangular, 
or star- shaped. 




Fig. 200. — The free form of thyroxin separated as a sheaf of needles. 



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426 E. C. KENDALL AND A. E. OSTERBERG 

precipitated by adding sulfuric acid to an aqueous alkaline solution 
and boiling, was found to contain 60 per cent of iodin. The difference 
in iodin content was shown to be due to the formation of a salt with 
sulfuric acid, and by estimating the molecular weight of thyroxin from 
the molecular weight of sulfuric acid, it was found to be 585. With 
hydrochloric acid substituted for sulfuric, an iodin content, slightly 
higher than theoretical, indicated that the hydrochlorid was hydro- 
lyzed to some extent. Thyroxin in free form precipitates as needles, 
but the hydrochlorid separates in flat, rectangular, and star-shaped 
plates. Examination of the crystals of the hydrochlorid, which 
• contained more iodin than theoretical, showed both the free form and 
the hydrochlorid. The sulfate of thyroxin does not hydrolyze with 
water so readily as the hydrochlorid (Figs. 199 and 200). 

Ultimate analysis of thyroxin gave the percentages of carbon, 
hydrogen, oxygen, nitrogen, and iodin, and from these and the molec- 
ular weight of determination of 585 the empirical formula was shown 
to be. CuHioOsNIs. In constructing the structural formula we were 
guided by the following: 

1. Acidic properties. — Thyroxin is readily soluble in sodium, 
ammonium, and potassium hydroxid, and is insoluble in sodium, 
ammonium, and potassium carbonate as ordinarily tested. It is 
soluble in aqueous sodium and potassium carbonate, however, if very 
little carbonate is added and the solution boiled. It is precipitated 
by carbon dioxid from an alkaline solution. The empirical formula 
and these acidic properties, therefore, suggest the presence of one 
carboxyl group, which has very weak acidic properties, and a hydroxy 
group. 

2. Basic properties. — Thyroxin forms salts with mineral acids, 
but not with weak organic acids. This, together with the fact that 
thyroxin forms a ureid with cyanic acid, is evidence for the presence 
of an imino group. The identification of the indol nucleus by the 
pine-splinter reaction after alkaline fusion was evidence that the 
imino group was present as in indol. Accepting the presence of the 
indol nucleus, there remained three extra* carbon atoms, a carboxyl 
group, a hydroxy group, three atoms of iodin, and three extra hydro- 
gen atoms, whose positions in the molecule were to be determined. 
Since tautomerism is common in the indol group, it seemed probable 
that the position of the hydroxy group was adjacent to the imino, and 
that the three carbon atoms including the terminal carboxyl were 



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THE CHEMICAL IDENTIFICATION OF THYROXIN 427 

attached to No. 3 position* of the indol nucleus. This structural 
formula, approximating that of tryptophane, satisfied all that was 
known concerning the chemical properties of the molecule except the 
position of the three iodin atoms and the three extra hydrogen atoms. 
As no special difference was demonstrable between the reactivity of 
the three atoms of iodin, it seemed most probable that they were 
all attached to the benzene ring, and as three extra hydrogen atoms 
would be required, if the iodin was added to, and not substituted for, 
hydrogen on the ring, they also were placed on the benzene ring. 
This formula is a tetra-hydro derivative of indol, the three atoms of 
iodin being substituted for three of hydrogen on the reduced benzene 
ring. 

jH/ c \ h h y> 

l cr N c c— c— c— of 

I H H \oh 

? C \c/ C \n/ C== ° 

H 

H 

Structural formula of thyroxin: 4, 5, 6 tri-hydro- 4, 5, 6 tri- 
iodo- 2 oxy-beta-indol-propionic acid. 



jH/^\ h h y> 

l cr N c c— c— c— cf 

I I H H \oh 



H | 

C=0 
I 
H— C— H 

I 
H 



In proving the formula the first derivatives were those involving 
the imino groups. By the addition of acetic anhydrid to a slightly 



•In this paper the positions in the indole nucleus will be referred to as follows: 

• 5 A_ s 

7 1 



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428 



E. C. KENDALL AND A. E. OSTERBERG 



alkaline, alcoholic solution of thyroxin, the hydrogen of the imino is 
replaced with acetyl and the acetyl derivative may he separated in 
crystalline form by the addition of sulfuric acid and water and the 
removal of the alcohol by boiling under diminished pressure. The 
sulfate of the acetyl of thyroxin is thus formed. This is dissolved in a 
small amount of alcohol and when added to boiling water the acetyl 





y - L J? 




m^m 


if*?* 


m 


^4 HI 




j 





Fig. 201. — The crystal form of the acetyl derivative of thyroxin. 

of thyroxin separates in pure form (Fig. 201). The melting point 
of the acetyl is slightly lower than that of thyroxin, it crystallizes in 
the form of needles more curved and much shorter than those of thy- 
roxin, and although thyroxin is insoluble in all organic solvents the 
acetyl is readily soluble in alcohol, ether,' ethyl-acetate, and dilute 
aqueous ammonia and pyridin. The close approximation, by analysis, 
of the theoretical percentage of iodin in the acetyl, 60.77, corroborates 
the molecular weight of 585. 



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THE CHEMICAL IDENTIFICATION OF THYROXIN 



429 



Another derivative of the imino group which is easily formed is 
the ureid. 



I r H 
I H / \ 



H 



H *y 
C— C— C— CZ 
H H \oh 



H 

N 

h/\h 

This is made by the addition of a salt of thyroxin, either the sodium 
or zinc salt, to acetic acid to which potassium cyanate has already been 




Fio. 202. — The crystal form of the ureid derivative of thyroxin. 

added. Cyanic acid reacts with thyroxin with the formation of the 
ureid. It separates from boiling water in curved needle form and has 
very closely the same solubilities as the acetyl (Fig. 202). Analysis 
of the ureid shows the percentage of iodin to agree with the theoret- 



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430 E. C. KENDALL AND A. E. OSTERBERG 

ical, 60.67. This is a third confirmation of the molecular weight 585. 
Although thyroxin forms a stable salt with sulfuric acid which is not 
hydrolyzed by boiling in dilute sulfuric acid, the addition of the acetyl 
of ureid groups to the imino increases the acidic properties of the 
imino, and these derivatives do not form stable salts with sulfuric acid 
except at low temperatures. Boiling the sulfate in dilute sulfuric 
acid causes a complete hydrolysis and separation of the acetyl or 
ureid in free form. The presence of the imino group in thyroxin is 
established by identification of the indol nucleus, the formation of the 
acetyl and ureid derivatives, and by the power to form salts with 
mineral acids. 

The evidence for the carboxyl and hydroxy groups is as follows: 
Thyroxin is extremely insoluble in aqueous solutions of all acids, in- 
cluding carbonic. It is vecy easily soluble in sodium potassium and 
ammonium hydroxid, but the weakness of the acidic groups on the 
molecule is shown by the fact that boiling water alone causes a com- 
plete hydrolysis of the ammonium salt and free thyroxin may be 
precipitated in crystalline form by boiling an aqueous or alcoholic 
solution of its ammonium salt. Dilute solutions of sodium and 
potassium carbonate will dissolve only a small amount of thyroxin in 
the cold, but it is soluble in very dilute solutions of sodium and potas- 
sium carbonate at 100°C. However, on cooling such a solution, a 
mono-metal salt of thyroxin separates in crystalline form. If an 
excess of carbonate is present at first, the mono-salt of thyroxin is so 
insoluble in the presence of the excess sodium or potassium carbonate 
that most of the thyroxin being tested remains insoluble. The addi- 
tion of a very slight amount of sodium or potassium hydroxid to a 
solution containing a suspension of thyroxin in the presence of sodium 
or potassium carbonate immediately carries the thyroxin into solu- 
tion. These reactions suggest that there are present in thyroxin both 
carboxyl and hydroxy groups. The carboxyl group reacts with car- 
bonates but the resulting mono-salt is so slightly soluble that the 
presence of excess carbonate forces the mono-salt out of solution. 
The hydroxy group in the presence of carbonates alone does not 
react, but the addition of hydroxid to such a solution forms a metal 
salt with the hydroxy group and the di-metal salt is readily soluble.^ 

Still further evidence for this action is found in the barium salt. 
Barium chlorid added to a sodium hydroxid solution of thyroxin 
precipitates thyroxin in needle crystals, usually twined, or in sheaves 



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THE CHEMICAL IDENTIFICATION OF THYROXIN 



431 



or bundles. If this is filtered off it is found to be slightly soluble in 
boiling water. On cooling and with the addition of a soluble barium 
salt to the solution, the barium salt of thyroxin recrystallizes 
quantitatively. If red litmus paper is dipped into a boiling aqueous- 
suspension of the barium salt, the solution reacts neutral, but wher- 
ever the crystals of the barium salt come in contact with the paper 
the color of the indicator is changed to blue, showing that hydrolysis 




Fio. 203.- 



-The mono-potassium salt of thyroxin which separates in small flat plates, 
rectangular, or square. 



of the barium salt has occurred. If sodium hydroxid is added to an 
aqueous suspension of the barium salt of thyroxin the barium salt 
is dissolved and becomes almost as soluble as the sodium salt. This 
behavior is explained by the fact that the second hydroxyl group 
of barium hydroxid is not sufficiently strong to form a soluble salt 
with the hydroxy group of thyroxin. In the presence of boiling water 
the hydroxy group of thyroxin and one hydroxy group of barium 
exist in free form, barium forming a salt only with the carboxyl 



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432 E. C. KENDALL AND A. E. OSTERBERG 

group of thyroxin. Both hydroxy and carboxyl groups are slowly 
hydrolyzed by prolonged boiling of the barium salt in water. 

The difference between the two acid groups is also shown in a 
sodium, potassium, or ammonium hydroxid solution of thyroxin. 
If carbon dioxid is bubbled through such a solution so as to produce 
sodium carbonate, but not bicarbonate, the hydroxy group is freed 
from metal and the mono-metal salt of thyroxin separates in flat 




Fio. 204. — The mono-ammonium salt of thyroxin which separates in long blades. 



crystals, oval, rectangular, or square. If an excess of carbon dioxid 
is passed through the solution, the carboxyl group also is freed and 
thyroxin will separate. The separation of the mono-sodium salt 
occurs at the point where the hydroxy group has been freed, but the 
carboxyl group is still in the form of a salt (Figs. 203 and 204). 

While endeavoring to separate the metal salts for analysis the 
mono-sodium, potassium, and ammonium salts of thyroxin were 
prepared by dissolving thyroxin in strong solution of the hydroxids 
and passing carbon dioxid through these until the mono-metal salt 
separated. The crystals were filtered on a small Buchner funnel, 



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THE CHEMICAL IDENTIFICATION OF THYROXIN 



433 



and washed with water. It was found that approximately 60 per 
cent of the amount of thyroxin taken way left on the funnel after 
drying in the supposed form of the mono-sodium, potassium, and 
ammonium salts. It was also found that if the salt was washed on 
the funnel with a 20 per cent solution of sodium or potassium chlorid, 
and not with water, the compound did not melt. When, however, 
the mono-salt was washed with water the sodium, potassium, and 




Fig. 205. — The di-silver salt of thyroxin which separates in large, flat, rectangular and 
square plates, often occurring in sheaf form and twined. 

ammonium salts all had the same melting point, 204°. Since the 
mono-salt of thyroxin does not melt and the sodium, potassium, and 
ammonium salts, washed with water, all melt at exactly the same 
point, it seemed probable that the washing with water was sufficient 
to hydrolyze the very weak carboxyl, with the result that free thyroxin 
was left on the paper, the base being entirely washed away. In 
order to determine this the mono-ammonium salt was prepared as 
above, filtered, and washed with water and then analyzed for ammonia 

'19— 2S 



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434 £. C. KENDALL AND A. E. OSTERBERG 

by means of nesslerization. Nesslerization, although an exceedingly 
sensitive test for ammonia, failed to show the presence of even the 
faintest trace of ammonia in the supposed mono-ammonium salt 
of thyroxin. It was therefore evident that by washing the mono- 
sodium, ammonium, and potassium salts of thyroxin with water 
the weak carboxyl group can be completely hydrolyzed, and since 
the hydroxy group already was in the free form, the molecule existed 
with both carboxyl and hydroxy groups uncombined with metal. 




Fig. 206. — The di-potassium salt of thyroxin which separates in flat plates with rough, 

irregular edges. 

Evidence that a di-metal derivative of thyroxin does form is 
furnished by the silver salt. Although a di-silver salt containing 
the theoretical amount of iodin has not been prepared, this salt 
has been made with so much silver present that it amounted to 92 
per cent of the theoretical for the addition of two atoms of silver 
to the molecule. The reason why the theoretical di-silver salt cannot 
be prepared is undoubtedly due to the weakness of the hydroxy group 
(Fig. 205). When the di-silver salt, which is highly crystalline, is 



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THE CHEMICAL IDENTIFICATION OF THYROXIN 485 

washed in order to remove the excess of silver nitrate 'and ammonia 
which are used in its formation, the hydroxy group*hydrolyzes to 
some extent, and the amount of silver remaining is slightly less than 
theoretical. 

Di-basic salts of sodium, ammonium, and potassium are formed 
by dissolving thyroxin in the respective hydroxids, and adding a 
corresponding salt of the alkali, preferably the chlorid, until the 
di-alkali salt of thyroxin becomes insoluble and precipitates in crystal 




Fio. 207. — The zinc salt of thyroxin which separates as long, flat blades in bundles and 

rosettes. 

form (Fig. 206). Di-basic salts, which are only slightly soluble, have 
also been prepared with barium, calcium, magnesium, nickel, zinc, 
and copper (Fig. 207). Although all these salts may be made in 
beautifully crystalline and characteristic form, it is impossible to 
filter and separate them in a high state of purity by washing with 
water. Just as hydrolysis of the hydroxy group caused a lower 
silver content than theoretical with the silver salt, the hydrolysis 
of the hydroxy group with the barium salt shows a lower percentage 



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436 E. C. KENDALL AND A. E. OSTERBERG 

of iodin than theoretical. However, the weight of barium added is 
about twice that required for the mono-metal &alt. With the less 
basic properties of calcium, magnesium, zinc, nickel, and copper 
even greater differences occur between the amount calculated for a 
di-metal salt and the amount found. But in every case since the 
amount of metal present nearly agreed with that required for a di- 
basic salt, the possibility that these are mono-basic salts is excluded. 
All salts of thyroxin which are insoluble in water such as the silver, 
copper, zinc, nickel, calcium, and magnesium are soluble in sodium 
hydroxid. The solubility is probably due to the same reactions 
that occur with the barium salt. The weak basic properties of the 
metals are insufficient to form soluble di-basic salts, but sodium 
hydroxid carries the salt into solution by adding to the hydroxy 
group of thyroxin. 

Other evidence for the carboxyl and hydroxy group is furnished 
by the dimethyl ester. Methyl iodid added to an alcoholic suspension 
of the silver salt forms the dimethyl ester. This is soluble in alcohol 
but insoluble in water even in the presence of sodium hydroxid. 
By heating in dilute alcoholic sodium hydroxid, hydrolysis of the 
methyl ester of the carboxyl occurs and the oxymethyl derivative is 
obtained. 

TAUTOMERIC FORMS OP THYROXIN 

Thyroxin reacts in the presence of alkalies, forming di-basic salts, 
but differences between the two acidic groups indicate that one is a 
carboxyl and one a hydroxy group. When thyroxin exists in this form, 
which will be called the enol, the hydroxy group is adjacent to the 
nitrogen, but there is a double-bond between the nitrogen and the 
alpha carbon, and no hydrogen is attached to the nitrogen. 

! C H O 

I C X C—Q—C—cf 

H H \ 0H 



Cv ^C v ,£— OH 



\An/ 



H 



In acid solution thyroxin forms derivatives, which demonstrate the 
presence of an imino group, and exists in its tautomeric form, with 
imino carbonyl groups adjacent. This will be called the keto form. 



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THE CHEMICAL IDENTIFICATION OF THYROXIN 



487 



When thyroxin was first isolated it was in the keto form and although 
it seemed probable that the hydrogen migrated in alkaline solution 
with a change from carbonyl to hydroxy groups, no quantitative data 
were available for proof of the hypothesis. When the mono-metal 
salts of sodium, ammonium, and potassium were prepared by freeing 
the hydroxy group in alkaline solution with carbon dioxid, it was 
found that by washing with water complete hydrolysis of the carboxyl 




Fio. 208. — The crystals of the enol form of thyroxin. 

also occurred. When the hydrolysis of the ammonium salt was carried 
out at 100° both acidic groups were not only freed but, in addition, 
the boiling water caused a change from the enol to the keto form. 
However, if the mono-metal salts are hydrdlyzed with cold water the 
enol form is retained. There are many differences in the chemical 
properties of the enol and keto forms, but the most striking difference 
is in the melting point. The melting point of the enol form is 204°, 
that of the keto, 250°. 



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488 E. C. KENDALL AND A. E. OSTERBERG 

When the enol form of thyroxin was prepared by cold hydrolysis 
of its ammonium salt, it still retained the crystal form of this salt, 
but by dissolving the crystals in pyridin and adding water the enol 
form separated in its own characteristic crystal form (Fig. 208). The 
enol form of thyroxin separates in needle crystals which are much 
shorter than those of the keto form and always occur in rosettes or 
sheaf-like byndles. Crystallization does not alter the melting point. 




Fio. 209. — The simultaneous crystallization of both enol and keto forms of thyroxin 
from an aqueous pyridine solution. 

The keto form of thyroxin is by far the more stable and, unless 
precautions are observed, the enol form readily passes over into the 
keto. The most important factors influencing the change from enol 
to keto form are the presence of water and the hydrogen ion concen- 
tration. By adding water to a pyridin solution of the enol form, 
conditions may be produced in which both enol and keto forms simul- 
taneously crystallize (Fig. 209) . On long standing, even at room tem- 
perature, the enol form slowly changes over to the keto and the keto 
form alone separates. Since the chief chemical properties of thyroxin 



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THE CHEMICAL IDENTIFICATION OF THYROXIN 4S9 

are due to its basic and acidic groups, a brief summary of solubilities 
and reactions of the two tautomeric forms is of interest. 

The enol form of thyroxin is much more soluble than the keto, 
and the solubility may be used as a test of the form in which thyroxin 
is present. For example, the keto form is insoluble in all organic 
solvents, such as all alcohols, ether, chloroform, ethyl acetate, acetone, 
carbon disulfid, quinolin, pyridin, anhydrous or aqueous, and anilin. 
The enol foim is readily soluble in anhydrous or aqueous pyridin. 
Therefore, pyridin alone is not sufficiently basic to change the keto 
into the enol form, but when this change has been produced pyridin 
readily dissolves thyroxin. Since ammonium hydroxid in water, 
alcohol, or p\ridin will change the keto form to the enol, but pyridin 
cannot produce this change, the hydroxyl ion concentration necessary 
for the conversion from one tautomeric form to the other lies between 
the basicity of dilute ammonium hydroxid and that of pyridin. Since 
the enol changes to the keto in a boiling aqueous pyridin solution, 
the acidity necessary for the tautomeric change in this direction lies 
between the narrow limits of the hydrogen ion concentration of a 
cold and a boiling aqueous solution of pyridin. The limits for the 
change in tautomeric form are at the same time the limits of solubility 
for thyroxin in alkaline solution. Thyroxin is soluble in enol form, in 
pyridin and quinolin, but any higher concentration of hydrogen ion 
causes the change to the keto form and limits the solubility of thyroxin 
in alkalies. Thyroxin in the keto form remains insoluble in all organic 
solvents with hydrogen ion concentrations equal to or less than that of 
glacial acetic acid. It is soluble in formic acid, but the subsequent 
addition of water causes thyroxin to separate again. Although acetic 
acid will not make thyroxin soluble in alcohol the addition of a mineral 
acid renders thyroxin readily soluble in alcohol. Solubility under 
these conditions is evidence for the formation of salts with the imino 
group. 

The acid and basic properties of thyroxin therefore lie between 
these two limits: (1) The formation of salts with acids through the 
imino group of the keto form with formic acid, but not acetic, and 
(2) the formation of salts with alkalies through both the carboxyl 
and hydroxy groups with dilute ammonia, but not with pyridin. 
Lying between these two limits are the formation of mono-metal salts 
through the carboxyl alone in the presence of carbonates, but not 
bicarbonates, and finally the complete precipitation of thyroxin from 



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440 E. C. KENDALL AND A. E. OSTERBERG 

the alkali metal salts by carbonic acid or by hydrolysis with water in 
a boiling ammoniacal solution. The mono-metal salts of thyroxin 
are but slightly soluble in water but are easily soluble in alcohol. The 
solubility in alcohol is due to the fact that although only the carboxyl 
group is combined with metal, the molecule is in the enol and not the 
keto form. 

The imino group of thyroxin reacts with all acids stronger than 
and including formic acid, but no acid salt of thyroxin is appreciably 
soluble in water, and even the sulfate which is the most soluble is only 
very slightly so. The great insolubility of the keto form of thyroxin 
is one of the most important factors permitting the isolation of the 
compound. The insolubility of thyroxin is also of importance in a 
consideration of its chemical properties. As soon as the proper con- 
ditions exist in any solution for the formation of the keto form of 
thyroxin, the reactive groups are thrown almost completely out of the 
sphere of reaction by the insolubility of the compound. 

The keto form of thyroxin is soluble in organic solvents only when 
some acid is present which is capable of forming an acid salt with 
the imino group. Thyroxin may be conveniently purified by dissolv- 
ing either in alkaline alcohol with the addition of acetic acid, or by 
dissolving in acid alcohol with the addition of sodium acetate. In 
the presence of acetic acid the imino group does not form a salt and 
thyroxin precipitates in needle form. 

OPEN-RING FORM OF THYROXIN 

Since thyroxin in keto form is insoluble in bases weaker than 
ammonium hydroxid and is insoluble in alcohol in the presence 
of acids weaker than formic, there is a wide range of hydrogen ion 
concentration^ in which pure thyroxin is insoluble. These limits 
of solubility, however, apply only to pure thyroxin in aqueous and 
alcoholic solutions. In the presence of certain substances, changes 
in the acid and basic groups occur and the solubilities of thyroxin are 
materially altered and extended. In the presence of the products 
resulting from alkaline hydrolysis of the thyroid proteins the solubility 
of thyroxin is so greatly altered that it is completely soluble in car- 
bonic acid, and even acetic acid produces an incomplete precipitation. 
Hydrochloric and sulfuric acids precipitate thyroxin under these 
conditions, hut in excess they redfr solve a considerable percentage of 



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THE CHEMICAL IDENTIFICATION OF THYROXIN 441 

the total amount present. The increased solubility in acids indicates 
an increase in the strength of the basic groups of the thyroxin molecule. 
Although pure thyroxin is practically insoluble in pyridin, sodium car- 
bonate, barium hydroxid, and alcohol, partially purified thyroxin 
is readily soluble in the presence of all these reagents. The increased 
solubility in weak alkalies indicates an increase in the strength of the 
acidic groups in the thyroxin molecule. These changes in the chemical 
properties of thyroxin are most marked during the early stages of 
purification while there is a large percentage of impurities present, 
but that the alteration is due entirely to the impurities is disproved by 
the fact that both increased acidic and basic properties persist even 
after the removal of all but a trace of the impurities. Furthermore, 
the addition of certain substances to a solution of pure thyroxin brings 
about a similar increase in both basic and acidic properties. The 
solubility of partially purified thyroxin in weak alkalies is in such 
striking contrast to the solubility of pure thyroxin that it cannot be 
explained except by a change in the structure of the niolecule other 
than the two tautomeric forms described above. The exact nature 
of this change was suggested by a study of the acetyl. 

In all derivatives of thyroxin involving the hydrogen of the imino 
group, it is impossible to make the enol form, as the hydroxy group 
cannot exist. Because of the absence of the hydroxy group these 
derivatives should form mono-basic salts through the carboxyl group 
alone, they should be more insoluble in alkalies, and should form in- 
soluble barium and silver salts. Since acid salts of the imino are 
soluble in alcohol, acetic acid, and ethyl acetate, it seemed probable 
that derivatives attached to the imino would also make the molecule 
soluble in these reagents. After the acetyl and ureid were prepared 
in pure form they were found to be easily soluble in alcohol, acetic 
acid, and ethyl acetate, but instead of being less soluble in alkalies, 
the acetyl was more soluble and could be held in solution with as weak 
a base as pyridin alone. 

The acetyl was not only more soluble in weak organic bases but 
it also formed a silver salt which was completely soluble in dilute 
ammonium hydroxid. The silver salt of thyroxin will separate 
from strong ammonium hydroxid, but the silver salt of the acetyl 
is so soluble that it is impossible to prepare it in the pre ence of am- 
monia. By dissolving the acetyl in p\ridin, however, the addition 
of silver nitrate produces a voluminous precipitate which may be washed 



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442 E. C. KENDALL AND A. E. OSTERBERG 

dried, and analyzed. When this was done it was found that the acetyl 
had formed a di-basic salt with silver. The formation of a di-basic 
salt by the acetyl indicated the presence within the molecule of an- 
other acidic group other than the terminal carboxyl. The simplest 
change by which a carboxyl group could be formed would be by intro- 
duction of a molecule of water between the imino and carbonyl groups, 
changing the imino carbonyl groups to amino carboxyl groups, and 
in the case of the acetyl the amino group is combined with one acetyl 
radical. 

H 5c? H H //O 

l q' x C C— C— C— Cf 

j | H H \oh 

H /\k 

The presence of the acetyl radical in place of the imino hydrogen 
prevents the tautomeric change to the enol form, but in place of this, 
the ring opens even in the presence of weak organic bases. The acetyl 
attached to the amino group, however, does not prevent the closure 
of the ring, and if an alkaline solution of the acetyl, which is present 
in the open-ring form, is added to a dilute mineral acid at 100°, the 
ring closes and the acetyl separates in crystalline form. In addition 
to the di-silver salt of the acetyl, the zinc salt has been made, and di- 
basic sodium, ammonium, and potassium salts of the open-ring form 
of the acetyl may be prepared by dissolving in the respective hydrox- 
ids and adding a corresponding salt, the chlorid or acetate, until 
the salt of the acetyl becomes insoluble (Figs. 210 to 21S). If sodium 
hydroxid and sodium acetate are used, very large, flat, jagged plates 
result; with sodium hydroxid and sodium chlorid short needle crystals 
are formed. 

Barium and calcium salts of the acetyl can also be formed by the 
addition of barium or calcium chlorid to a solution of the acetyl in 
dilute sodium hydroxid or pyridin. An excess of pyridin dissolves 
the salt. 

After the physical and chemical properties of the acetyl deriva- 
tive had been established, it was found that a most striking resem- 
blance existed between partially purified thyroxin and the acetyl. 



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THE CHEMICAL IDENTIFICATION OF THYROXIN 44S 




Fio. 210. — The di-sodium salt of the acetyl derivative separated from a sodium chlorid 

solution. 




Fio. 211. — The di-sodium salt of the acetyl derivative separated from a sodium acetate 

solution. 



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444 



E. C. KENDALL AND A. E. OSTERBERG 




Fio. 212. — The di-potassium salt of the acetyl derivative. 




Fig. 213. — The di-potassium salt q( the ureid of thyroxin which separates in a manner 
similar to the di-potassium salt of the acetyl derivative. 



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THE CHEMICAL IDENTIFICATION OF THYROXIN 445 

The acetyl differs from thyroxin in having wider limits of solubility 
in weak bases, and the greatest difference between partially purified 
and pure thyroxin is the solubility of the former in the weaker alkalies, 
sodium carbonate, barium hydroxid, pyridin, and in alcohol. These 
reactions suggested that in partially purified thyroxin the structure 
of the molecule is similar to that of the acetyl. But the possibility 
that an acid radical was attached to the imino group, as in the acetyl, 
could be excluded by the fact that the thyroxin could be separated 
in keto form. The increase in both acidic and basic properties, its 
close resemblance in chemical reactions to the acetyl, and the fact that 
it could be separated in the keto form suggest that in partially purified 
thyroxin the molecule is present neither in the keto nor enol forms, 
but that the pyrrol ring exists in open form, the elements of water 
entering between the carbonyl and imino groups. 

This structure of the molecule of thyroxin will be called the open- 
ring form. The open-ring form of indol derivatives containing an 
alpha carbonyl group is of common occurrence, but thyroxin is perhaps 
unique in the great ease with which the ring opens and the great diffi- 
culty with which the ring closes in the presence of certain substances. 

Although the open-ring structure of thyroxin was first suggested 
by a study of the acetyl, further investigation has amply confirmed 
this hypothesis and brought to light the delicately balanced reactions, 
which, in all probability, are involved when the substance functions 
physiologically. These reactions are concerned with the opening and 
closing of the ring and the formation of salts with acids by the amino 
and imino groups. When sulfuric acid is added to a slightly alkaline 
alcoholic solution of thyroxin and the alcohol is distilled, the sulfate 
of thyroxin separates, the sulfate radical being attached to the imino 
group. However, if sulfuric acid is added to an alkaline aqueous 
solution of thyroxin, the resulting precipitate is not the imino sulfate 
of thyroxin. Analysis of this precipitate for its iodin content showed 
that thyroxin had not precipitated in free form but contained one 
equivalent of acid. Further investigation showed that thyroxin preci- 
pitates with one equivalent of acid, not only with sulfuric but with 
weak organic acids and that even carbonic acid adds to thyroxin when 
carbon dioxid is passed through an alkaline solution. The sulfate, 
chlorid, phosphate, trichloracetate, oxalate, formate, acetate, and car- 
bonate of thyroxin have been prepared. All these salts are soluble in 
alcohol and have melting points which are strangely similar, all of them 



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446 E. C. KENDALL AND A. E. OSTERBERG 

melting at about 204°. Although the imino group of thyroxin in keto 
form is so feebly basic that in hot dilute hydrochloric solution the acid 
radical is hydrolyzed and the imino group exists in free form, when 
the enol form of thyroxin is precipitated by an acid, an equivalent of 
acid is contained in the precipitate attached to thyroxin. If any of 
these salts, prepared by acidifying an alkaline solution of thyroxin, 
are moved from solution, suspended in distilled water, and boiled, 
a change occurs, and thyroxin precipitates in long, bundle blades. 
These blades differ from the keto form of thyroxin in being soluble in 
alcohol and having a melting point of 225°. If instead of suspending 
the acid salts in distilled water, they are added to a dilute solution 
of hydrochloric or sulfuric acid and are then boiled, the keto form of 
thyroxin separates. These reactions are interpreted as follows: 

When an acid is added to the enol form of thyroxin, the nitrogen 
becomes pentad and the acid radical adds to the nitrogen. In aqueous 
solution the pyrrol ring is no longer stable and the elements of water 
add between the pentad nitrogen and the carbonyl group, form- 
ing a carboxyl group and an acid salt of the amino group. In cold 
water solution this reaction occurs not only with sulfuric and strong 
organic acids, such as trichloracetic and oxalic, but even carbonic 
acid is capable of adding to the amino group. 

jH/ c \ h h y> 

1 C / N C- — C— C— C— cf 



H H \ H 



H N ~ H O 

H \ 

c=o 

R 



When the amino salt is suspended in distilled water and boiled, the 
amino group is hydrolyzed free from the acid, and the carboxyl group 
which is adjacent to the amino group forms a salt with the amino 
group. The compound then exists in an amino carboxyl salt form, 
the acid used in precipitating thyroxin having been expelled from 
the amino group by hydrolysis with water. 



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THE CHEMICAL IDENTIFICATION OP THYROXIN 



447 






H H •" 

c— c— c— cf 

H H \, 



,0 



OH 



C=0 

/ 



H \ N ' " 

/1\ 
H H H 

This form of thyroxin differs from both the keto and enol forms in 

having the addition of the elements of water. It has a melting point 

of 225° and is soluble in alcohol (Fig. 214). It is converted into the 




Fio. 214. — Crystals of thyroxin in the amino carboxyl form. 

keto form very easily; merely solution in alcohol is sufficient to expel 
the water, and the keto form of thyroxin then separates. It is im- 
possible to separate the amino carboxyl salt form of thyroxin from 
solutions containing a high percentage of alcohol. Further investi- 
gation showed that this is also true of pyridin and other organic 
solvents. It is necessary to have water present in order to force 
the opening of the pyrrol ring. • 



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448 



E. C. KENDALL AND A. E. OSTERBERG 




Fig. 215. — Crystals of the amino carbonate of thyroxin. 







* 


i 






W 


•w^ 


■jfi 


% 


i 



Fig. 216. — A mixture of the crystals of the amino formate changing into the amino enr- 
boxyl salt form of thyroxin. The long needles are the amino carboxyi crystals. 



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THE CHEMICAL IDENTIFICATION OF THYROXIN 449 

If any acid salt of the amino group of the open-ring form of thyroxin 
is suspended in distilled water and boiled, the carboxyl group in 
thyroxin, which is adjacent to the amino, will displace the acid radical 
attached to the amino, and the amino carboxyl salt form of thryoxin 
results. If the acid radical which is added to the amino is sufficiently 
strong and an excess of the acid is present, the ring does not remain 
open, but the elements of water are expelled and the strong acid radical 




Fxo.|217. — A mixture of amino carboxyl crystals changing into the keto form of thy- 
roxin. The long needles are crystals of the amino carboxyl form of thyroxin. 

is either hydrolyzed from the imino group or remains attached as an 
acid salt of the imino group. The closing of the ring of an amino- 
acid salt is influenced by many factors, such as the amount of acid 
present, the strength of the acid, and the presence of organic solvents, 
such as pyridin or alcohol. Strong acids promptly close the ring, 
forming imino salts; weak acids are expelled from the amino, and the 
molecule exists in the amino carboxyl form. The presence of organic 
solvents such as alcohol results in the closing of the ring and the 
formation of imino salts with strong acids, or the displacement of 

'19—29 



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450 E. C. KENDALL AND A. E. OSTERBERG 

the acid with the separation of thyroxin in keto form. If an ami no- 
acid salt of the open-ring form is washed free from all acid, suspended 
in neutral water, and boiled, the acid is promptly hydrolyzed from the 
amino group and the amino carboxyl salt form results, but in the 
absence of excess acid in solution this form of thyroxin is unstable at 
100°C, water is rapidly expelled from the ring, and the keto form of 
thyroxin separates in very fine thread-like crystals. Under proper 
conditions all three forms may be present at the same time (Figs. 
215 to 217). 




Fig. 218. — The imino sulfate of thyroxin separated from a hot solution 

Since acids added to the enol form of thyroxin in aqueous solution 
cause an opening of the ring, the question arose as to whether the 
opening of the pyrrol ring is the primary action, or whether it is 
secondary to the existence of the nitrogen in the pentad form. That 
the opening of the ring occurs without passing through the enol form 
is shown by the formation of the amino sulfate directly from the 
imino sulfate (Figs. 218 and 219). When the imino sulfate is present in 
a small amount of alcohol and water is added, the ring opens and the 



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THE CHEMICAL IDENTIFICATION OF THYROXIN 451 

amino sulfate separates even though the molecule had existed in the 
keto form. The formation of amino salts from imino salts shows that 
the ring opens readily when the nitrogen is in the pentad state, but 
that the opening of the ring also occurs directly from the enol form in a 
solution slightly alkaline may also be shown. When the di-sodium 
salt of thyroxin is dissolved in cold water and ammonium chlorid 
is added to the solution, the sodium is hydrolyzed from hydroxy 




Fig. 219. — The amino sulfate of thyroxin formed from the imino sulfate of thyroxin 
by the addition of water to an alcoholic solution of imino sulfate. 

and carboxyl groups, resulting in the precipitation of thyroxin in the 
enol form. If this suspension of the enol form is now boiled the 
crystal form changes into the typical amino carboxyl salt form, the 
melting point of which is 225°. The crystals are also readily soluble 
in alcohol, which excludes the possibility of their being in the keto 
form. A more direct evidence of the existence of thyroxin in open- 
ring form is obtained by dissolving the di-sodiuin salt in hot water and 
adding ammonium chlorid to this hot solution. Instead of thyroxin 



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452 



E. C. KENDALL AND A. E. OSTERBERG 



separating in the enol form, it separates directly as the amino carboxyl 
salt form. The most important factor in this reaction is the presence 
of excess alkali. If much alkali is present, the molecule exists in the 
enol form and addition of ammonium chlorid will cause a separation 
of the mono-ammonium salt. 

From these results it would appear that in acid alcohol solutions 
thyroxin exists in the keto form. In the presence of excess alkali 
in aqueous solution thyroxin exists in the enol form, but as the neutral 
point is reached from either direction there is a tendency for the ring 
to open. In a hot neutral solution the ring does open. In a cold 
neutral solution even carbonic acid will open the ring and add to the 
amino group. 




Fig. 220. — The crystals of the amino hydrate form of thyroxin. 
THE AMINO HYDRATE FORM OF THYROXIN 

The pyrrol ring of thyroxin not only has a tendency to take up 
water between the imino and carbonyl groups and exist in amino 
carboxyl form, but the amino group is so strongly basic that in a 



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THE CHEMICAL IDENTIFICATION OF THYROXIN 



453 



slightly alkaline solution the elements of water will add to the nitrogen 
forming the amino hydrate. 



i H / c \ 



H -?-c/° 



c— c— v.— v.< 
i H H \ 



*k\ ^Cv //C-OH 



H /\ 

HO H 



OH 




Fig. 221. — A mixture of enol and keto forms of thyroxin crystallizing simultaneously 

from the same solution. 



This form of thyroxin is tautomeric with the amino carboxyl form. 
It is very readily prepared by heating an alkaline solution of thyroxin, 
removing the solution from the flame, and adding 10 per cent am- 
monium chlorid. The solution becomes turbid, and fine branching 
crystals separate (Fig. 220). The melting point of this form of thy- 
roxin is 216°. If these crystals are suspended in distilled water 
containing a small amount of formic acid and the solution is boiled, 



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454 



E. C. KENDALL AND A. E. OSTERBERG 



the crystals are changed into their tautomeric amino carboxyl form, 
whose melting point is 225° (Figs. 221 and 222). 

One form of thyroxin changes into another so easily that enol 
and keto forms will crystallize simultaneously out of the same solution 
and amino-acid salt, amino carboxyl salt, and keto forms may all be 
present at the same time, one form changing into another as the boiling 
of the solution is continued. The ready change of thyroxin from one 




Fig. 222. — A mixture of the crystals of the amino carboxyl form changing into 
the keto form. The small rosettes are crystals of thyroxin in the keto form. 

form to another is explained by the great ease with which the pyrrol 
ring opens and the elements of water are added to the molecule. 
This reaction does not occur with indol or isatin and was not at first 
easily explained in the case of thyroxin. While engaged in the pre- 
paration of the intermediate products for the synthesis of thyroxin, 
our attention was drawn to the fact that the explanation of the 
peculiar properties of the imino group in the pyrrol ring of thyroxin 
is the presence of the hydro groups in the benzene ring. Anilin is a 
feeble base and the imino group in indol is still more feebly basic. 



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THE CHEMICAL IDENTIFICATION OF THYROXIN 455 

Hexa-hydro-anilin has such a strongly basic amino group that it 
will combine with carbon dioxid from the air, and it has a very caustic 
action on the skin. It is the addition, therefore, of four hydro groups 
to the molecule that so modifies the nucleus, giving basic properties 
to the imino group of the pyrrol ring of thyroxin. Speculation as to 
the properties of the compound in which the three iodins are replaced 
by three hydrogens may be deferred until the substance is prepared 
synthetically, but that the imino group of the pyrrol ring will be still 
more basic in this compound would naturally follow from the general 
law that addition of halogen to the benzene ring renders the ring more 
acidic. The position and reason for the three extra hydrogens in 
thyroxin were unknown and were very puzzling until the reactions 
of the compound involving the amino and imino groups caused 
the necessity of explaining this action by some modification of the 
indol nucleus. Since the introduction of the six hydro groups in 
anilin greatly increases the basicity of the amino group, the addi- 
tion of four hydro groups to the irdol nucleus of thyroxin is an ade- 
quate explanation of the inci eased basicity of its amino group. The 
instability of the pyrrol ring of thyroxin in contrast to that of indol 
and other unreduced derivatives of pyrrol is due to the increased basic 
properties of the nitrogen in thyroxin. This point is well illustrated 
in the stability of the amino carboxyl form. In neutral solution the 
nitrogen tends to become triad, the pyrrol ring is more stable than the 
amino carboxyl salt, and thyroxin separates in keto form. If a slight 
amount of acid is present, the nitrogen remains in the pentad state 
and the amino carboxyl form is so stable that it is impossible to expel 
water from the molecule and make the keto form. The difference in 
the basicity of the nitrogen when changing from the open- to the 
closed-ring forms is probably involved when thyroxin functions 
physiologically. But the unique chemical properties of thyroxin 
are also due in large measure to the carbonyl group adjacent to 
the imino, and the reactivity of the substance in vivo and in 
vitro is due to the presence of this oxy group in the indol nucleus. 
It was for this reason that the compound was named thyro-oxy-indol 
or thyroxin. 

After it was found that thyroxin forms amino salts with feeble 
carboxyl groups, it was of especial interest to form the amino salt of 
thyroxin with glycin. Reserving a study of the reaction between 
thyroxin and the amino-acids for a further communication, merely the 



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456 E. C. KENDALL AND A. E. OSTERBERG 

formatioD of an amino-acid salt between thyroxin and glycin will 
be reported in this paper. 

Since acid added to the enol form of thyroxin results in the 
formation of an amino salt, it seemed probable that at least a portion 
of the nitrogen of thyroxin should react as amino nitrogen with 
nitrous acid when the molecule existed in the amino-acid salt form. 
This was tried and it was found that when an alkaline aqueous 
solution of thyroxin was added to a Van Slyke amino-acid apparatus, 
approximately 70 per cent of the total nitrogen present was liberated 
as amino nitrogen. When the keto form of thyroxin was used, no 
nitrogen was evolved. When the amino carboxyl form of thyroxin 
is added to nitrous acid, about 15 per cent of its total nitrogen is 
evolved as amino nitrogen. The reason that a quantitative evolu- 
tion of amino nitrogen does not occur with the last mentioned form 
in three minutes is because the crystals are insoluble and the reaction 
takes place at a very slow rate. 

When nitrous acid is added to an alcoholic solution or to an 
aqueous suspension of thyroxin in the presence of hydrochloric acid, 
a yellow color is produced. Upon the addition of ammonia this is 
changed to a deep red which in dilute solution is pink. This color 
reaction is convenient for a rough qualitative test for thyroxin. How- 
ever, if acetic or sulfuric acid is used in place of hydrochloric, a fainter 
yellow color is produced, and the addition of ammonia gives a yel- 
lowish orange instead of a red color. 

During the purification of thyroxin, the presence of colloidal 
impurities is sufficient to cause the opening of the ring and also to 
prevent the closing of the ring. When an alkaline solution of thyroxin 
is acidified the precipitate carries down many of the impurities present 
as salts of the amino group and hence no quantitative separation can 
be effected by precipitation with an acid. The chief problem in the 
isolation of thyroxin is to close the ring in the presence of the impurities, 
and thereby produce chemical properties specific to the thyroxin 
molecule, which permit of a separation. This difficulty in closing the 
open-ring form of thyroxin is well illustrated in the course of its puri- 
fication. Approximately 50 per cent of the iodin content in the early 
steps of the separation of thyroxin is soluble in barium hydroxid. 
This barium-soluble portion may be hydrolyzed by heating with 
barium hydroxid for many hours, precipitated with acid, given another 
treatment with barium hydroxid, and this process continued as 



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THE CHEMICAL IDENTIFICATION OF THYROXIN 45? 

many as seven or eight times without rendering thyroxin insoluble 
in barium hydroxid. This treatment, however, slowly separates 
many of the impurities and the percentage of iodin in the dry material 
may reach as high as 58 per cent. Thyroxin in this open-ring form 
contains sufficient impurities to impart a distinctly yellow color, and 
it is readily soluble in sodium carbonate, barium hydroxid, pyridin, 
and alcohol. By chance such a preparation was dissolved in sodium 
carbonate solution and was allowed to stand seven weeks. At the 
end of that time a white residue had separated and settled to the 
bottom of the flask. Examination showed this to be the mono- 
sodium salt of thyroxin. Although the material was in the open-ring 
form when dissolved in the carbonate, on long standing the ring had 
closed and the compound thereby became insoluble in sodium car- 
bonate. 

The open-ring form of thyroxin cannot be precipitated from 
alcohol with acetic acid. The keto form of thyroxin is very nearly 
quantitatively precipitated from alcohol by acetic acid, but as long 
as impurities are present, an alcoholic solution of the open-ring form 
of thyroxin may be allowed to stand several weeks without the separa- 
tion of any trace of thyroxin. If, however, an alcoholic solution of 
thyroxin is slowly evaporated on the water bath, the evaporation causes 
a partial separation. A yellow oily tar creeps up the inclined bottom 
of the evaporating dish and forms a ring as the alcohol evaporates. 
At the spot where the last trace of alcohol was left, a dry crusty 
material, which is almost white, shows the partial separation of thy- 
roxin in the keto form. This property of thyroxin to separate from 
alcohol, even in the presence of impurities, is the reaction by which 
thyroxin was first isolated. The alcohol in this case was evaporated 
unintentionally, and, although the entire sample of thyroxin had been 
completely soluble in the alcohol, the slow evaporation and subse- 
quent heating at 100° was sufficient to close the ring in a small percent- 
age of the total amount with the result that it was insoluble on the 
addition of more alcohol. This method of separation is not of great 
value for the isolation of the compound. The best method so far de- 
termined for the closing of the ring is to dissolve thyroxin in alcohol 
containing sodium hydroxid, and pass carbon dioxid through the solu- 
tion, freeing both hydroxy and carboxyl groups. Most of the sodium 
carbonate is insoluble and is removed by filtration. The alcohol is 
distilled, leaving an aqueous sodium carbonate solution of thyroxin, 



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458 E. C. KENDALL AND A. E. OSTERBERG 

but still in open-ring form. Allowing this to stand for several days will 
cause a separation of the mono-sodium salt in the enol form which may 
be purified by similar treatment. 

OXIDATION AND REDUCTION OF THYROXIN 

Quantitative oxidation and reduction experiments with thyroxin 
have not been carried out because of the amount of material which would 
be required in order to isolate .the products. Thyroxin is more 
susceptible to reduction than to oxidation. Zinc in alkaline or acid 
solution bieaks off iodin and appears to alter the organic nucleus. 
Thyroxin is reduced when heated in the presence of any metal in 
alkaline solution other than nickel, and the heavy metals, silver, gold, 
and platinum. Thyroxin is stable in the presence of mild oxidizing 
agents. Hydrogen peroxid pioduces no immediate effect and in a 
cold acid suspension the molecule will resist oxidation with potassium 
dichromate or iodic acid. Potassium permanganate or bromin in 
hot aqueous solution causes the breaking down of the molecule. 
Benedict's copper solution, for the determination of sugar, causes 
an oxidation of thyroxin in the presence of sodium hydroxid. In 
the presence of ammonium hydroxid alone, thyroxin is stable in 
Benedict's solution heated to boiling. Free iodin if added to an 
alkaline solution produces a precipitate and apparently brings about a 
deep-seated reaction within the molecule. In acetic acid or acid 
alcohol, iodin has very little, if any, effect on thyroxin even at the tem- 
perature of boiling acetic acid. Further investigation showed that, 
in the presence of iodin, thyroxin is stable in the keto form, but not in 
the enol form. The changes produced by oxidation with chlorin, 
bromin, and iodin have not been determined, but in alkaline solu- 
tions yellow tarry products are formed. Since the enol form of 
thyroxin is so much less stable than the keto, the weakness in the 
molecule appears to be in the linkage of the nitrogen, and the point 
of cleavage is probably between the nitrogen and the hydroxy groups. 
When the imino carbonyl groups are present, the molecule is much 
more resistant to oxidation by halogen. 

Another point of weakness within the molecule exists in the ben- 
zene ring. The completely reduced benzene ring readily passes over 
into a six carbon, straight chain form. Hexo-hydrophenol may be 
readily oxidized to adipic acid by the action of dilute nitric acid. In 
thyroxin the benzene ring is in the tetra hydro form, and it is highly 



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THE CHEMICAL IDENTIFICATION OF THYROXIN 459 

probable that the one double bond which is present will break down 
with the formation of an open chain structure. A reaction similar to 
this is found in the oxidation of the tetra-hydro-benzene ring of 
sedanonic acid 1 to straight chain acids. 

Due to the weakness of the linkages to the nitrogen in thyroxin, 
it is impossible to hydrolyze derivatives from the imino group. After 
the acetyl radical has been attached to the imino group, it cannot be 
hydrolyzed with sodium or potassium hydroxid. When treated 
with alkali, the compound precipitates as a di-metal salt, and is thrown 
out of solution. If sufficiently drastic action is applied to bring about 
the hydrolysis, disruption of the molecule occurs. 

Thyroxin upon exposure to the sunlight in weak alkaline solution 
is very unstable. Within twenty-four hours the solution changes 
from colorless to a pink, or faint yellow, which deepens on standing to a 
brown color, depending on the amount of thyroxin present. Simul- 
taneously with the discoloration a distinct aromatic odor is produced 
slightly resembling that of nicotin. Such a solution, when tested for 
iodin by means of starch in acid solution, shows that no iodin has 
been broken off in the free form. If, however, a small amount of 
potassium iodid is added, iodin is immediately liberated, which 
indicates that the iodin within the thyroxin molecule was not broken 
off either as hydriodic acid or as iodin, but in the form of hypo-iodous 
acid. On longer standing a test for free iodin is given without the 
addition of potassium iodid and the amount of hypo-iodous acid is 
much reduced. After several weeks no test for iodin or hypo-iodous 
acid is given, but all the iodin is found in the form of hydriodic acid. 
The reduction of the hypo-iodous acid to hydriodic acid is probably 
brought about by the hydro-indol nucleus. The finding that iodin 
is broken off from the thyroxin molecule in the form of hypo-iodous 
acid and not as hydriodic has direct bearing on the physiologic action 
of the molecule within the body. 

THE ACETYL DERIVATIVE 

With the acetyl, sunlight produces a similar reaction, but in 
this case the solution is found to contain both hypo-iodous acid and 
iodin. The acetyl derivative, therefore, is more susceptible to oxida- 
tion than thyroxin, and brings about a much more rapid reduction of 
the hypo-iodous acid to iodin and hydriodic acid. 



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460 E. C. KENDALL AND A. E. OSTERBERG 

So unstable is the acetyl under certain conditions that there is a 
spontaneous liberation of iodin from the molecule and the simul- 
taneous oxidation of the organic nucleus, resulting in a change of 
color and the production of a yellow tarry material. The conditions 
under which it is produced appear to be in a solution of approximately 
the neutrality of distilled water. If barium or calcium chlorid is 
added to a sodium hydroxid solution of the acetyl, and the solution 
is boiled, no decomposition of the barium or calcium salts occurs. 
If magnesium chlorid is used in place of barium or calcium, the basi- 
city of magnesium hydroxid is insufficient to prevent the decomposi- 
tion of the acetyl, and there is a spontaneous liberation of iodin 
accompanied with production of a blue color, which changes to green, 
and finally to yellow. This same reaction occurs if the sodium salt 
of the acetyl is dissolved in distilled water and allowed to stand without 
the addition of sodium hydroxid. Also if the di-sodium salt is filtered 
on a small Buchner funnel, washed with sodium chlorid, and allowed 
to stand in a moist condition, there is rapid liberation of iodin and 
production of bluish green colors, which fade to yellow. If small 
pieces of the acetyl in dry form are added to water, alcohol, or pyridin 
containing alkali, the solution of the solid material is accompanied 
by decomposition in part with a liberation of iodin and discoloration. 
If the acetyl is dissolved in alcohol the addition of sodium hydroxid 
to the solution will form the sodium salt of the acetyl without de- 
composition or liberation of iodin. Furthermore, an alkaline solu- 
tion can be added to acid with precipitation of the acetyl without 
decomposition. In both acid and alkaline solutions the acetyl is as 
stable as thyroxin, but at the neutral point a spontaneous decomposition 
occurs. One of the factors which affects this reaction is the mass of 
material present. In dilute solutions the decomposition of the acetyl 
is very much slower, and in sufficiently dilute solutions it may not 
occur at all. This effect of the mass of material explains why solution 
in alcohol prevents the destruction of the acetyl with addition of 
alkali. The mechanism is essentially the diminution of the concen- 
tration of the acetyl. Great difficulty was encountered in the prepara- 
tion of the acetyl until the factors influencing the decomposition were 
discovered. As thyroxin does not react in this way no difficulty was 
anticipated, and it was only after identification of free iodin in the 
solutions of the acetyl which had turned bluish green that an insight 
into the mechanism was obtained. Why the acetyl derivative spon- 



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THE CHEMICAL IDENTIFICATION OF THYROXIN 461 

taneously decomposes at the neutral point and gives' off iodin in the 
free form instead of hypo-iodous acid, as occurs with thyroxin, is not 
known. 

The reactions resulting in the oxidation of the acetyl and libera- 
tion of iodin are also given by the ureid under similar conditions. 
This excludes the possibility that the acetyl radical is necessary for 
the decomposition and suggests that the reason for the instability is 
the replacing of the imino hydrogen by a larger group. 

When this decomposition has occurred in part, the products 
cannot be removed from the rest of the material, and it is impossible 
to separate the acetyl in free form. The tarry products resulting 
from the decomposition of a small part prevent the crystallization 
of the rest of the acetyl. The retention of impurities by the acetyl 
is very similar to the retaining of impurities by partially purified 
thyroxin. 

Beside the spontaneous decomposition other reactions which 
are specific to the acetyl were found which will be discussed at this 
time. It was found that when the acetyl is freshly precipitated 
from an alkaline solution by an acid it is soluble in ether. After it 
has been separated in crystalline form and dried it is insoluble in 
ether. This difference in solubility is undoubtedly due to the acetyl 
existing in open-ring form when precipitated from cold water solution. 
The closed-ring form is insoluble in ether. 

When the acetyl derivative is prepared by adding acetic anhydrid 
to an alkaline alcoholic solution of thyroxin and the alcoholic solution 
of the acetyl is then added to ether, the acetyl is removed only partially 
by subsequent extraction of the ether with sodium hydroxid. A large 
amount of the acetyl remains in the ether. If the ether solution is 
tested with nitrous acid the usual reaction, with the production of a 
yellow color turning to red with the addition of ammonia, does not 
occur. After alcoholic sodium hydroxid is added and the solution is 
heated, a typical reaction with nitrous acid will take place. Another 
difference of the acetyl before and after the treatment of the ether 
solution with alkali is shown in the solubility of the acetyl in alkalies. 
If the ether is evaporated before alkaline hydrolysis, the acetyl is 
found to be very difficultly soluble in aqueous sodium hydroxid. After 
hydrolysis in alkaline alcohol the acetyl is very easily soluble in dilute 
alkali. The non-reactivity with nitrous acid and insolubility in alkali 
may be due either to the formation of an inner salt between the car- 



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462 E. C. KENDALL AND A. E. OSTERBERG 

boxyl and imind, or to the formation of a di-acetyl derivative. Treat- 
ment with alkalies hydrolyzes either the acid salt or one acetyl group, 
and the acetyl in free form is liberated. 

THE ACTION OF SUNLIGHT ON THYROXIN, AND THE PRODUCTION OF 
COLORED COMPOUNDS FROM THYROXIN 

When thyroxin, the acetyl, or the ureid is dissolved in dilute 
sodium hydroxid and allowed to stand in the sunlight, the solu- 
tion slowly changes, and in the course of from twelve to seventy-two 
hours develops a distinctly pink color. On further standing the 
pink color is changed to yellow. When the carbonic acid derivative 
was prepared by treating thyroxin with phosgene, it was found to be 
unstable and changed to a deep pink. When the sodium or barium 
salt of thyroxin is allowed to stand exposed to sunlight in a dry form, 
it also develops a pink color. With the barium salt this action does 
not occur in the dark, or when the salt is covered with water. The 
development of the pink color in each case is accompanied by the 
splitting off of iodin in the form of hypo-iodous acid. This pink color 
was first noticed on the edges and outside of white porcelain casseroles 
which were used to extract the barium salt of thyroxin with sodium 
hydroxid. Where the solution dried and was exposed to heat and 
light the pink color developed. Later this was shown to be due to the 
thyroxin itself and not to the impurities present. The chemical 
structure of the pink-colored compound is still unknown, but it appears 
probable that it is an oxidation product of the hydro-indol nucleus. 
The effect of light on the separation of thyroxin is of importance, and 
loss of thyroxin due to the action of light may amount to a considerable 
percentage of the total unless precautions are observed not to permit 
the action of direct sunlight to destroy the partially purified thyroxin. 

EFFECT OF ACID AND ALKALI ON THYROXIN 

No quantitative determinations have been made as yet concern- 
ing the ultimate products of alkaline hydrolysis because of the amount 
required to isolate the decomposition products. Thyroxin is not 
affected at room temperature by any concentration of aqueous sodium 
hydroxid. It is soluble in dilute alkali and after the concentration 
has reached from 10 to 15 per cent the di-sodium salt separates. The 
further addition of alkali renders the sodium salt more insoluble but it 
does not cause any destruction of thyroxin. Although thyroxin is 



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THE CHEMICAL IDENTIFICATION OF THYROXIN 463 

stable in sodium hydroxid at room temperature, when it is heated 
above 110° in the presence of strong sodium hydroxid, there is a 
destruction of the molecule with the splitting off of sodium iodid, and 
eventually the liberation of indol which may be identified by the pine- 
splinter reaction. The amount of indol liberated is not quantitative 
and it is probable that only traces of the hydro-indol nucleus appear as 
indol. 

In acids thyroxin is not so stable as in the presence of alkali. 
In aqueous solutions of pure thyroxin, hydrochloric or sulfuric acids 
precipitate the hydrochlorid or sulfate of thyroxin, and, since these 
are insoluble, the destruction of thyroxin is prevented. However, 
when thyroxin is present in open-ring form, strong acids bring about 
reactions with the impurities, and oily tarry products result. In 
alcohol solutions prolonged action of hydrochloric acid causes a de- 
struction in part even with pure thyroxin, resulting in the production 
of a brown discoloration. Polymerization of indol compounds in the 
presence of acid is well established, and it seems probable that this 
explains the destructive action of acids on thyroxin. 

A CONSIDERATION OF OTHER POSSIBLE STRUCTURAL FORMULAS 

Accepting the empirical formula as C11H10O3NI3, the carbonyl 
group in the molecule could be present as a ketone, either attached to 
the side chain or to the benzene ring. That this is not the case is 
shown by the failure of thyroxin to react with hydrazin, phenylhydra- 
zin, or semicarbazone. The carbonyl group adjacent to the imino 
should not react with hydrazin and the failure of thyroxin to react 
is evidence corroborating the hypothesis that the carbonyl group 
is adjacent to the imino. The positions of the three iodin atoms, 
the three extra hydrogen atoms, and the three carbon atoms in excess 
of the indol nucleus have not been determined by substitution or by 
decomposition products. The most conclusive proof of the position 
of the three carbon atoms and the terminal carboxyl would be furnished 
by the synthesis of thyroxin. The synthesis of thyroxin will be 
reported in another paper, but at this time the synthesis of the com- 
pound will be cited as evidence for the correctness of the structural 
formula assigned in regard to the position of the three carbon atoms 
with terminal carboxyl. The establishment of the fact that thyroxin 
does not rotate polarized light excludes an asymmetric carbon atom 
and confirms the arrangement of the double bonds. 



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464 



E. C. KENDALL AND A. E. OSTERBERG 



THE CRYSTAL FORM AND MELTING POINT OF THYROXIN 

The keto form of thyroxin crystallizes in six distinctly different 
forms (Figs. 223 to 228). Each of the seven other forms of thyroxin 
has characteristic crystal forms. The di-basic and mono-basic metal 
salts and the amino- and imino-acid salts of thyroxin also have char- 
acteristic forms. 




Fios. 223 to 228. — Six different types of crystals in which the keto form of thyroxin 

separates. 

The crystal forms of imino-acid salts and of di-metal and mono- 
metal salts are flat plates for the most part. The other crystal forms 
are long branching needle blades or thread-like needles which occur 
in rosettes or sheaves, or in tangled masses. 

Beside the type of crystal, all these forms and derivatives of thy 
roxin also have characteristic melting points. For these reasons 
microscopic study of the crystals and the determination of the melt- 
ing point are the two methods which have proved of greatest value 
during this investigation. The determination of iodin is not of such 



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THE CHEMICAL IDENTIFICATION OF THYROXIN 



465 



value because the iodin content of any one form may vary within 
wide limits without greatly affecting either the melting point or the 
crystal form. A good illustration of this is in the ketoform of thyroxin. 
The keto form of thyroxin when pure melts at 250°, when slightly im- 
pure the melting point drops to 246° or 245°, and when grossly con- 
taminated with impurities it drops to 240°. This point, however, 
appears to be the limiting value below which the keto form seldom 




Fio. 224. 

melts. It appears that merely dissolving thyroxin in alkali and pre- 
cipitating it causes a slight decomposition. The decomposition pro- 
ducts are retained by the pure thyroxin and are separated with great 
difficulty. However, the presence of these impurities rarely exceeds 
the amount which lowers the melting point to the neighborhood of 
240°. Microscopically the keto type of crystals could be identified, 
and the melting point of 240° or above would confirm the form in 
which thyroxin existed but the iodin content might vary as much 
as 2.5 per cent from the theoretical. The melting point of the keto 

' !(►— 30 



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466 



E. C. KENDALL AND A. E. OSTERBERQ 



form, from 240° to 250°, is the highest of all forms or derivatives of 
thyroxin. The amino carboxyl form melts in the neighborhood of 
225°; the amino hydrate melts at 216°, and the enol form at 204°; 
the imino-acid salts melt at about 228°; the amino-acid salts in the 
neighborhood of 204°; the derivatives of thyroxin attached to the im- 
ino, in closed-ring form, melt at about 238° and in open-ring form at 
about 152°. It is apparent that the melting points of different forms 




Fig. 225. 

and derivatives are so widely separated that no misinterpretation 
could result except in cases of mixtures, and the crystal form is so defi- 
nite that mixtures can be identified under the microscope. It has 
been found, however, that the melting point varies greatly with the 
rate of heating. One sample of thyroxin which melted at 240° when 
heated at the rate of 10° increase per minute, melted at 248° when 
heated at the rate of 18° increase per minute, and at 221° when heated 
at the rate of 0.6° increase per minute. 



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THE CHEMICAL IDENTIFICATION OF THYROXIN 467 




Fig. 226. 




Fig. 127. 



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468 



E. C. KENDALL AND A. E. OSTERBERG 



For a routine determination we have adopted the rate of 10° 
increase per minute, and when the melting point is observed under 
these conditions each form of thyroxin and its derivatives agree very 
closely in their melting points, with other samples of the same form. 



■ 



* 44 



Fig. 228. 



EXPERIMENTAL 



The percentage of iodin in thyroxin 

Eighteen different samples of thyroxin have been prepared, the 
weights of the samples ranging from 900 mg. to 5 gm. All the samples 
contained at least 63.5 per cent of iodin and six were purified until 
they contained approximately 65 per cent of iodin. The iodin content 
of Samples 1 to 6 is as follows: 



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THE CHEMICAL IDENTIFICATION OF THYROXIN 



469 



Sample 1. 


5.10 mg. 


contained 


3. SI 


" 2. 


5.12 " 


«i 


3.32 


3. 


5.24 " 


«< 


3.41 


" 4. 


5.10 " 


u 


3.32 


5. 


25. S " 


" 


16.45 


" 6. 


4.51 " 


M 


2.66 



Iodin Content of Thyroxin* 

3 . 31 mg. of iodin = 64 . 81 per cent. 
64.86 
65.02 
65.00 
65.00 
65.02 

Solubility = one part in 48,800. 

Precipitation of thyroxin from alkaline alcohol with acetic acid, or 
by boiling an ammoniacal solution, does not vary the percentage of 
iodin. Precipitated with acetic acid fiom alkaline alcohol the iodin 
content of thyroxin was 64.95 per cent. Precipitation of the same 
preparation by boiling an ammoniacal solution gave an iodin content 
of 64.92 per cent. Fifty milligrams of thyroxin were dissolved in 200 
c.c. of water containing 3 c.c. of concentrated ammonium hydroxid. 
The solution was boiled down to 100 c.c. One hundred cubic centi- 
meters of water were added and the solution was boiled for a few 
minutes, cooled, and filtered. Fifteen cubic centimeters of filtrate 
contained 0.20 mg. of iodin. 



Ultimate Analysis of Thyroxin 



Sample No. 

7 
7 
8 
9 



Weight of 

sample. 

mg. 



201.4 
171.2 
201.0 
124.2 



Carbon 

dioxid, 

mg. 



175.2 
148.0 
248.8 
101.9 



Water, 
mg. 



Carbon 
per cent 



Hydrogen 
per cent 



32.3 
26.9 
45.7 
18.5 



23.72 
23.57 
23.32 
22.37 



1.78 
1.74 
1.74 
1.65 



Iodin 
per cent 



64.95 
64.95 
64.92 
65.02 



102 mg. of thyroxin contained 2.27 mg. nitrogen = 2.23 per cent. 



Carbon 
per cent 



Calculated for CuHioOiNIi I 22 .56 

Found I 22.37 



Hydrogen 
per cent 



1.70 
1.65 



Oxygen 
per cent 



8.20 
8.73 



Nitrogen 
per cent 



2.39 
2.23 



Iodin 
per cent 



65.10 
65.02 



2 The iodin was determined by a method published in 1914, which has been modi- 
fied recently so that it is now applicable for the determination of small amounts of iodin 
to a high degree of accuracy (Kendall, E. C. : The determination of iodine in connec- 
tion with studies in thyroid activity, Jour. Biol. Chem., 1914, xix, 251), 



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470 E. C. KENDALL AND A. E. OSTERBERG 

SOLUBILITY OF KETO FORM OF THYROXIN 

Fifty milligrams of thyroxin were dissolved in 200 c.c. of dilute 
sodium hydroxid. Twenty cubic centimeters of 50 per cent hydro- 
chloric acid were added and the solution was boiled; 15 c.c. of the 
filtrate contained 0.116 mg. of iodin. 

Solubility = one part in 84,000. 

The sulfate of thyroxin. — For the preparation of the sulfate 50 
mg. of thyroxin are dissolved in 200 c.c. of water containing 50 to 100 
mg. of sodium hydroxid ; 20 c.c. of 50 per cent sulfuric acid are added, 
and the solution is boiled. The sulfate of thyroxin is soluble at 100°, 
but on cooling settles to the bottom of the container in oval-shaped 
plates. It may be filtered on a Buchner funnel, washed with water, 
and dried in a desiccator. 

Analysis of the Sulfate of Thyroxin 
Sample 1. 5.48 mg. contained 3.27 mg. of iodin = 59.71 per cent 
2. 25.00 " " 15.00 " " " =60.00 

114.4 mg. of thyroxin sulfate gave 86.9 mg. of carbon dioxid, 18.1 mg. of water; 
5.08 mg. contained 3.04 mg. of iodin. 

Carbon I Hydrogen ' Iodine 
per cent ' percent I per cent 



Calculated for CnHnOfiNIaSj | 20.82 | 1.73 ' 60.09 

Pound 20.71 1.75 59.92 

Fifty milligrams of thyroxin were dissolved in 200 c.c. of sodium 
hydroxid precipitated with 20 c.c. of 50 per cent sulfuric acid, and the 
solution was boiled; 15 c.c. of the cooled filtrate contained 0.127 mg. 
of iodin. 

Solubility = one part in 76,900. 

The hydrochlorid of thyroxin. — The hydrochloride of thyroxin is 
best prepared by dissolving a small amount of thyroxin, 15 to 25 mg., 
in 5 or 6 c.c. of alcohol containing 2 to 3 c.c. of 50 per cent hydrochloric 
acid. One to two cubic centimeters of water are added, and the 
alcohol is boiled off in a test-tube. After most of the alcohol has been 
distilled the hydrochlorid will separate in flat, glistening plates. If 
too small an amount of acid is used, or too much water, the hydro- 
chlorid will hydrolyze, and the plates will change to needles. 

The metal salts of thyroxin. — Dry crystalline thyroxin is readily 
soluble in sodium and potassium hydroxids in the cold, if the concen- 
tration of the alkali is less than 10 to 15 per cent. Thyroxin is in- 



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THE CHEMICAL IDENTIFICATION OF THYROXIN 471 

soluble in sodium or potassium hydroxid in the cold if the alkali is 
stronger than 15 to 20 per cent, but it is more soluble in strong alkali 
if the solution is warmed. In a mixture of 66 per cent of alcohol and 
33 per cent of water containing 1 per cent of sodium hydroxid, thy- 
roxin may be dissolved to the extent of about 4 per cent. It is still 
more soluble in hot solutions, but on cooling will separate as the di- 
metal salt. Thyroxin is not readily soluble in dilute ammonia, but 
concentrated ammonia will dissolve about 1.8 per cent of thyroxin. 

The di-basic sodium and potassium salts. — One hundred milli- 
grams of thyroxin are dissolved in 20 c.c. of dilute sodium hydroxid 
and to this are added 150 c.c. of a solution of 10 per cent sodium 
hydroxid containing 20 per cent of sodium chlorid. If a precipitate 
occurs the solution is warmed and the clear solution is then allowed to 
stand until cold. The exact concentrations of sodium chlorid and 
hydroxid are not important. The di-sodium salt readily separates in 
any solution containing a high concentration of sodium salts. If the 
strongly alkaline solution is decanted and replaced with 15 per cent 
sodium chlorid solution, the crystals may be filtered through a Buchner 
funnel on paper. They are insoluble in 10 to 15 per cent sodium chlo- 
rid and may be washed and dried. The di-sodium salt cannot be pre- 
pared in pure form for analysis as washing with water dissolves the 
salt, and it passes through the paper. The di-basic potassium salt is 
prepared in a manner similar to that used for the sodium salt. The 
di-ammonium salt is prepared by dissolving thyroxin in hot concen- 
trated ammonium hydroxid and allowing the solution to cool. Flat, 
rectangular crystals of the di-ammonium salt will separate. 

The alkaline earth salts of thyroxin. — The barium, calcium, and 
magnesium salts of thyroxin are prepared by dissolving 50 to 100 mg. 
of thyroxin in 100 c.c. of dilute sodium hydroxid, using as small an 
amount of alkali as possible to carry the thyroxin into solution. The 
solution is heated to boiling and 20 c.c. of a 20 per cent solution of 
barium, calcium, or magnesium chlorid are added to the hot solution 
of thyroxin. Carbon dioxid is excluded by placing the beaker in an 
atmosphere free of carbon dioxid. The magnesium and calcium 
salts are very slightly soluble in boiling water. Five hundred cubic 
centimeters of boiling water will dissolve between 100 and 150 mg. 
of the barium salt. The barium salt may be suspended in boiling 
water and the solution filtered through a Buchner funnel into a suction 
flask. Thirty cubic centimeters of 20 per cent barium chlorid are 



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472 



E. C. KENDALL AND A. E. OSTERBERG 



now added to the filtrate and the barium salt allowed to recrystallize. 
Only a negligible amount of thyroxin is soluble in the presence of this 
amount of barium chlorid. The barium salt under these conditions 
is unstable and will slowly turn a pink color. Analysis for iodin 
shows a lower iodin content than that calculated. 

Iodin Content of Barium Salt 

Sample 1. 6.72 mg. contained 3.26 mg. of iodin = 48.51 per cent. 
" 2. 5.98 " " 3.00 " " " =50.24 

Calculated for BaC 11 H 8 0,NI l : 52.91 per cent. 

If the barium salt is filtered and dried there is a slow decom- 
position and the color of the salt becomes yellowish gray. 

Silver, copper, nickel, and zinc salts of thyroxin. — The silver, 
copper, nickel, and zinc salts are prepared by dissolving 50 to 100 
mg. of thyroxin in 25 to 50 c.c. of concentrated ammonia. Twenty- 
five cubic centimeters of a 10 per cent solution of silver nitrate, copper 
sulfate, nickel sulfate, or zinc sulfate are made ammoniacal with 
strong ammonia so that the precipitated hydroxid is just carried into 
solution, and there is a slight excess of ammonia. The solution of the 
metal is now added to the ammoniacal solution of thyroxin, and 
after standing a short time the crystals of the metal salt will separate. 
If too much ammonia is used, a larger amount of the solution of the 
metal may be required to start the crystallization. Allowing it to 
stand over night will insure a more complete precipitation. Sodium 
hydroxid may be used for the solution of thyroxin, but, since the 
metal salt of thyroxin is more soluble in sodium hydroxid, ammonium 
hydroxid has taeen found to be the most satisfactory solution. The 
silver, copper, nickel, or zinc salts suspended in water or dilute ammonia 
are soluble on the addition of several cubic centimeters of 30 per cent 
sodium hydroxid solution. 

Iodin Content op Silver Salt 
Sample 1. 4.86 mg. contained 2.37 mg. of iodin = 48.74 per cent. 



it 


2. 


4.96 " 




«t 


2.44 " 


t* «< 


= 49.15 


«( 


3. 


4.00 " 




<t 


1.97 " 


« <t 


= 49.34 


" 


4. 


4.06 " 




" 


1.99 " 


t «i 


= 49.10 


it 


5. 


4.54 " 




" 


2.23 " 


t tt 


= 49.20 


tt 


6. 


4.08 " 




«< 


1.96 " 


4 <« 


= 48.00 


" 


7. 


6.02 " 




" 


2.93 " 


t « 


= 48.60 


tt 


8. 


4.38 " 




<< 


[2.09 " 


" 


= 47.73 


Calculated for Ag 2 Cn 


H, 


O.NI. 






47.74 


tt 




" AgCnHiOiNIi: 






55.06 



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THE CHEMICAL IDENTIFICATION OF THYROXIN 473 

The average of these eight determinations is 48.73 per cent iodin. 
The iodin content indicates the addition of 9£ per cent of the theoret- 
ical amount for a di-metal salt and 184 per cent of the amount required 
for a mono-metal salt. The higher iodin content than that cal- 
culated for a di-metal salt is undoubtedly due to the hydrolysis of the 
hydroxy group. In the zinc salt, the amount of iodin was found to 
be 56.95 per cent. The calculated amount for the zinc salt is 58.79 
per cent, but the calculated amount of iodin in the zinc salt in which 
hydrolysis of the hydroxy group had occurred would be 57.12 per cent. 
The close agreement between the amount found and the latter figure 
is evidence that hydrolysis of the hydroxy group also occurs in the 
zinc salt of thyroxin. The low iodin content of the salts of the diad 
metals, barium and zinc, and the high iodin content of the salt of 
the monad metal, silver, suggest that in all di-metal salts of thyroxin 
hydrolysis of the hydroxy group is brought about by washing the salt 
with water. 

Preparation of monometal salts. — One hundred milligrams of 
thyroxin are dissolved in 150 c.c. of 1 per cent sodium hydroxid, and 
carbon dioxid is bubbled through the solution until thyroxin is pre- 
cipitated. The suspension is now heated until solution is complete. 
On cooling, the mono-sodium salt separates in crystal form. The 
separation of the mono-salt is assisted by the presence of sodium salts 
and is hindered by too great a dilution. An excess of carbon dixid 
must not be passed through the solution, as free thyroxin will be 
precipitated. The preparation of the potassium salt is similar to 
that of the sodium salt. In preparing the ammonium salt, strong 
ammonium hydroxid is much better than dilute, as the solubility 
of the ammonium salt is thereby decreased. If the mono-metal salt 
is filtered on a Buchner funnel and washed with 10 to 15 per cent 
sodium, ammonium, or potassium chlorid, it is not dissolved through 
the paper. If washed with cold water, about 40 per cent is dissolved 
and 60 per cent of the amount of thyroxin taken remains on the paper 
in the form of free thyroxin in the enol form. 

NESSLEBIZATION OF THE HYDROLYZED MONO-AMMONIUM 
SALT OF THYROXIN 

Fifty milligrams of the residue left on the paper after washing the 
mono-ammonium salt with water were dissolved in 60 c.c. of ammonia- 
free water containing a small amount of sodium hydroxid. The 



Digitized by VjOOQLC 



474 E. C. KENDALL AND A. E. OSTERBERG 

addition of 15 c.c. of Nessler's solution and dilution to 100 c.c. produced 
no color, showing that hydrolysis of the mono-ammonium salt was 
complete. 

Solubility of mono-sodium salt. — Five cubic centimeters of 0.10 per 
cent sodium carbonate dissolved about 15 mg. of dry thyroxin in keto 
form, when the solution was heated to boiling. Most of the thyroxin 
reprecipitated on cooling to 20°, but not as the mono-sodium salt. 
The crystals were needles or very small rosettes. One cubic centimeter 
of the filtrate contained 0.76 mg. of iodin = 1.J7 mg. of thyroxin. 

Solubility = one part in 850. 

Five cubic centimeters of 1 per cent sodium carbonate dissolved 
85 to 90 mg. of thyroxin at almost the boiling point. Probably more 
than this amount could be dissolved but as the solution began to turn 
yellow the heating was stopped. On cooling to 23°, needles in clusters 
and square plates of mono-sodium salt separated. One cubic centi- 
meter of filtrate contained 1.14 mg. of iodin = 1.75 mg. of thyroxin. 

Solubility = one part in 570. 

The enol form of thyroxin. — The enol form of thyroxin is the most 
difficult to prepare in crystalline form, but is very easily prepared in 
the crystal form of the mono-metal salts by cold water hydrolysis 
of the mono-ammonium sodium, or potassium salts. Ten to twenty 
milligrams of the enol form in dry powder is readily soluble in 1 to 2 c.c. 
of pyridin. The addition of 10 to 15 c.c. of water will produce a 
cloudiness. On long standing (twenty-four hours), the thyroxin will 
precipitate. Depending on conditions of the concentration of pyridin 
and the amount of thyroxin present, the thyroxin may precipitate in 
keto form. This may be distinguished under the microscope as long 
bundles, or sheaves of needles. The enol form separates in either 
rosettes or short bundles of needles. The enol form of thyroxin is also 
soluble in quinolin. Other ways to prepare the enol form of thyroxin 
is to add ammonium chlorid to a cold solution of the di-sodium salt 
in water which does not contain an excess of alkali, or to dissolve the 
di-sodium salt of thyroxin in alcohol and add water and ammonium 
chlorid. A mixture of both keto and enol crystals usually results if 
much alcohol is present. 

Ten to fifteen milligrams of dry crystals of the keto form of thyroxin 
may be boiled with 5 to 10 c.c. of pyridin without going into solution. 
The addition of a very small amount of dilute ammonia will change 
the thyroxin to the enol form and carry it into solution. The water 



Digitized by VjOOQLC 



THE CHEMICAL IDENTIFICATION OF THYROXIN 475 

may then be boiled off and the enol form remains soluble in pyridin. 
If 15 to 20 mg. of the enol form of thyroxin are dissolved in 2 to 3 cc. 
of pyridin in a test-tube, and to this 10 to 15 c.c. of water are added, 
and the solution is boiled, after the pyridin has been removed by dis- 
tillation, thyroxin will separate in the keto form similar to the pre- 
cipitation of thyroxin from a boiling ammoniacal solution. 

Twenty-five milligrams of thyroxin added in the keto form to 10 c.c. 
of water in the presence of 1 gm. of sodium carbonate will not dissolve. 
If alcohol is used instead of water and the alcohol is boiled, the sodium 
carbonate does not dissolve but the thyroxin is carried into solution. 
The mono-sodium salt of thyroxin in the enol form produced by the 
alcoholic suspension of sodium carbonate is readily soluble in alcohol. 

The amino-acid salt form of thyroxin. — For the preparation of 
amino-acid salts, thyroxin is dissolved in a small amount of sodium 
hydroxid in a large volume of water, and to this carbon dioxid or 
other organic acid is added until thyroxin precipitates. The volumi- 
nous precipitate is filtered, washed, and dried. In order to prepare 
the amino salts in crystalline form, other expedients may be used. 
For the preparation of the amino sulfate, thyroxin is dissolved either 
in formic acid or in alcohol containing a small amount of sulfuric acid. 
The alcohol is concentrated to small volume, and water is quickly 
added in large volume. 

SOLUBILITY OF THYROXIN IN AMINO-SALT FORM 

Hydrochlorid. — Fifty milligrams of thyroxin were dissolved in 200 
c.c. of dilute sodium hydroxid, and precipitated at 25°C. with a slight 
excess of hydrochloric acid; 15 c.c. of the filtrate, after removing the 
pi ecipitate of thyroxin, containing 0.037 mg. of iodin. 

Solubility = one part in 263,000. 

Carbonate. — Fifty milligrams of thyroxin were dissolved in 200 c.c. 
of dilute sodium hydroxid, and precipitated by passing carbon dioxid 
through the solution; 15 c.c. of the filtrate contained 0.012 mg. of iodin. 

Solubility = one part in 815,000. 

Iodin Content op Amino Carbonate 

5.8 mg. contained 3.137 mg. of iodin = 50.57 per cent. 
Calculated for CnHuOiNIsCHjCOa)^ = 60.09 per cent. 

The slightly higher figure for iodin than the calculated amount 
is probably due to separation of the thyroxin in either the enol or 



Digitized by VjOOQLC 



476 E. C. KENDALL AND A. E. OSTERBERG 

amino-hydrate form, or to the hydrolysis of the amino carbonate and 
formation of the amino carboxy). This sample of thyroxin contained 
65.02 per cent of iodin when precipitated in keto form. . 

The amino carboxyl form of thyroxin. — The amino carboxyl form 
is prepared by suspending the amino-acid salt form of thyroxin in 
water in the presence of a small amount of weak organic acid, such as 
acetic, and boiling the solution. The acid radical is expelled from the 
amino group, and the adjacent carboxyl group forms an amino car- 
boxyl salt. It can also be prepared by dissolving the di-sodium salt 
of thyroxin in a large volume of water, heating to boiling, adding 
ammonium chlorid, and continuing the boiling. The amino carboxyl 
form of thyroxin separates. 

If no acid is present the elements of water may be expelled from 
the molecule and thyroxin will separate in keto form. 

IODIN CONTENT OF HYDROLYZED AMINO-ACID SALTS 

A sample of amino carbonate was suspended in neutral distilled 
water and the solution was boiled three minutes. This was not suffi- 
ciently long to complete the hydrolysis. 

Five and thirty-eight hundredths milligrams contained 3.821 mg. 
of iodin = 61.72 per cent. The same sample boiled fifteen minute 
showed that all the carbonate had been expelled and also that some 
of the amino carboxyl form had been converted into the keto form. 

Five and two-tenths milligrams contained 3.305 mg. of iodin = 
63.56 per cent. A sample of amino sulfate suspended in distilled water 
and boiled more nearly approximated the amino carboxyl form, but 
in this case all the sulfate radical was not hydrolyzed. 

5.0 mg. contained 8.135 mg. of iodin = 62.72 per cent. 
Calculated for amino carbonate: 60.09 " " iodin. 

" " sulfate: 58.43 " " 

" carboxyl: 63.18 " " 

Preparation of the amino hydrate form. — Thyroxin is dissolved in 
a large volume of water with a moderate excess of sodium hydroxid. 
The solution is heated to boiling and then removed from the flame, 
and 10 per cent ammonium chlorid is slowly added to the amount 
of 10 to 15 c.c. The solution becomes turbid, and long branching 
crystals separate. The limits of the concentration of the hydrogen 
ion and the temperature for the formation of the enol, amino hydrate, 



Digitized by VjOOQLC 



THE CHEMICAL IDENTIFICATION OP THYROXIN 477 

amino carboxyl, and the keto forms are very narrow. If thyroxin 
is dissolved in a few milligrams of sodium hydroxid, and the solution 
is diluted to about 400 c.c., and divided into four equal parts, each 
of the four different forms of thyroxin may be prepared from these 
solutions merely by varying the conditions of the precipitation. 
Ammonium chlorid added to one of the solutions in the cold will 
precipitate the thyroxin in the enol form, or as the mono-ammonium 
salt in flat plates. If ammonium chlorid is added to the second 
solution, which has been heated to boiling, and then removed from 
the flame the amino hydrate form will separate. If the amino hydrate 
is precipitated in the third, and the solution containing a suspension 
of the amino hydrate is heated to boiling and the boiling continued, 
the crystals will change into the amino carboxyl form. If a large 
excess of ammonium chlorid is added to the fourth solution, and the 
solution is boiled, thyroxin will separate in the keto form. 

Open-ring form in the presence of impurities. — The percentage 
of iodin in the open-ring form of thyroxin, which is still soluble in 
pyridin, sodium carbonate, barium hydroxid and alcohol, may be 
between 50 and 60 per cent. 

Iodin Content of Thyroxin Still in Open-ring Form 

Sample 1. 5.00 mg. contained 2.51 mg. of iodin =50.28 per cent 

" 2. S.92 " " 2.13 " " " =54.21 " " 

S. 6.44 " " 3.51 " " " =54.46 " " 

4. 4.16 " " 2.43 " " " =58.53 " " 

The solubility of these samples in alcohol, sodium carbonate, and 
barium hydroxid showed that although the amount of impurities 
present was very small, the ring still existed in open form. 

Colloidal substances producing the open-ring form of thyroxin. — 
Fifty to 100 mg. of pure thyroxin, added to the impurities which are 
separated during the process of purification, will become readily 
soluble in alcohol, sodium carbonate, and barium hydroxid, showing 
the change from the keto to the open-ring form. Gelatin and proteins 
of blood produce the same changes, but the amino-acids resulting 
from the hydrolysis of gelatin will not change the solubility of thyroxin 
in barium hydroxide, alcohol, or sodium carbonate. 

THE ACETYL DERIVATIVE 

Preparation of the acetyl. — In the preparation of the acetyl it 
is necessary to use pure thyroxin. The presence of even a small 
amount of impurities makes it impossible to crystallize the acetyl 



Digitized by VjOOQLC 



478 



E. C. KENDALL AND A. E. OSTERBERG 



and it will separate only as an oily tar. One hundred milligrams of 
pure thyroxin are added to £0 c.c. of alcohol containing 100 mg. of 
sodium hydroxid. After the thyroxin is entirely dissolved 2 c.c. of 
acetic anhydrid are added. The solution is allowed to stand thirty 
minutes, 5 c.c. of water and 5 c.c. of 50 per cent sulfuric acid are 
added, and the alcohol is evaporated by boiling in a 200 c.c. distilling 
flask under diminished pressure. The temperature is not allowed 
to go above 40°C. Crystals of the sulfate of the acetyl separate as 
the alcohol is removed. These are dissolved in about 15 c.c. of alcohol 
which is filtered and added to a beaker containing £00 c.c. of boiling 
water and 5 c.c. of 50 per cent sulfuric acid. The addition of the first 
few drops of the alcohol solution of the acetyl does not cause a precipi- 
tate, but further addition of the alcohol solution causes a precipitation 
in crystalline form of the free acetyl. 

Purification of the acetyl may also be carried out by dissolving 
the acetyl sulfate in £5 c.c. of alcohol and adding 5 gm. of sodium 
acetate and 10 c.c. of 30 per cent sodium hydroxid. After the alcohol 
has been removed by boiling under diminished pressure, the di-sodium 
salt of the acetyl will separate in large, flat plates. The sodium salt 
may then be dissolved in alcohol and precipitated by addition to a 
boiling solution of dilute sulfuric acid as described above. 

Many samples of the acetyl have been prepared and analyzed. 
Some of the results are as follows: 

Analysis of the Acetyl op Thyroxin 

Sample 1. 5.26 mg. contained 3.20 mg. of iodin 

3.17 " " " 
1.90 " " " 
3.11 " " " 
3.14 " " " 
3.11 " " " 
3.09 " " " 
3.05 " " " 
3.05 " " " 

97.9 mg. of acetyl gave 90.1 mg. of carbon dioxid and 16.2 mg. of water; 5.10 mg. 
contained 3.10 mg. of iodin. 



2. 


5.20 


3. 


3.12 


4. 


5.12 


5. 


5.16 


6. 


5.10 


7. 


5.10 


8. 


5.04 


9. 


5.02 



= 


60.91 


per 


cent. 


= 


60.96 


" 


4* 


= 


60.85 


c< 


M 


= 


60.67 


it 


U 


= 


60.83 


«( 


«« 


= 


60.93 


" 


«• 


= 


60.61 


« 


•« 


= 


60.52 


« 


« 


s= 


60.74 


«t 


<« 



Carbon 
per cent 



Hydrogen 
per cent 



Iodin 
per oent 



Calculated for C13H13O4XI3. 
Found 



24.88 
25.09 



1.93 
1.85 



60.77 
60.86 



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THE CHEMICAL IDENTIFICATION OF THYROXIN 479 

The sulfate of the acetyl derivative. — If the acetyl derivative is 
dissolved in alcohol and added to boiling dilute sulfuric acid, the 
acetyl precipitates in free form without the addition of sulfuric acid 
attached to the imino group. If, however, sulfuric acid is added to 
the alcohol solution of the acetyl and the alcohol is evaporated at 
either room temperature, by a current of air or by boiling under 
diminished pressure at a low temperature, the sulfate of the acetyl 
separates in needle crystals. 

Analysis of the Sulfate of the Acetyl 

Sample 1. 5.02 mg. contained 2.84 mg. of iodin =56.66 per cent. 
" 2. 5.52 " " 3.12 " " " =56.52 ". " 

" 3. 6.2 " " 3.51 " " " = 56.61." " 

111.5 mg. of the sulfate of the acetyl gave 94.8 mg. of carbon dioxid and 19.7 mg 
of water; 5.52 mg. contained 3.12 mg. of iodin. 



Carbon 
per cent 



Calculated for CisHnOeMtS) 23.07 

Found I 23.18 



Hydrogen Iodin 



per cent 

1.92 
1.91 



per cent 

56.36 
56.52 



Although thyroxin is insoluble in pyridine, alcohol, ethyl acetate, 
or acetic acid, the acetyl is soluble in all of these reagents. When 
the acetyl is precipitated from an alkaline solution by the addition 
of an acid, it is at first soluble in ether and may be extracted out of the 
water by placing in a separatory funnel with ether. After the acetyl 
has been prepared in pure form and dried, it is insoluble in ether. 

The di-metal derivatives of the acetyl. 3 — The sodium, ammonium, 
and potassium salts of the acetyl are prepared as with thyroxin. One 
hundred milligrams of the acetyl are dissolved in 10 c.c. of alcohol, to 
which are added 10 c.c. of 30 per cent sodium hydroxid and 5 gm. of 
sodium acetate. The di-metal salt will separate in large, flat crystals 
if the alcohol is evaporated under diminished pressure. The tempera- 
ture may be raised to that of boiling water without decomposition 
of the acetyl by the sodium hydroxid as no hydrolysis of the acetyl 
occurs under these conditions. If sodium ch!orid is substituted for 

a In working with the acetyl, it is always necessary to dissolve the dry powder 
in alcohol before making it alkaline. Unless this is done, some of the acetyl will spontan- 
eously decompose during the solution of the powder in alkali. 



Digitized by VjOOQLC 



480 E. C. KENDALL AND A. E. OSTERBERG 

sodium acetate in a solution similar to the one mentioned above and 
the alcohol is evaporated, the sodium salt of thyroxin separates in 
small plates. 

The barium and calcium salts of the acetyl are prepared by dis- 
solving 25 to 50 mg. of the acetyl in the least possible amount of 
alcohol, 2 to 3 c.c., adding water and 0.5 to 1 c.c. of pyridin ; the solution 
is boiled until the alcohol is volatilized, care being taken not to decom- 
pose the acetyl by prolonged boiling. To the pyridin solution of the 
acetyl a 40 per cent solution of barium or calcium chlorid is slowly 
added, and the solution is heated to boiling. The alkaline earth salt 
of the acetyl will separate. It is readily soluble in an excess of pyridin. 
If the solution is heated for too long a time hydrolysis will occur. 
The salt may be filtered and washed without decomposition. 

The reactions of thyroxin indicate that the molecule exists jn 
both open- and closed-ring forms. The chemical properties of the 
acetyl are evidence that this derivative also exists in open- and closed- 
ring forms. The sodium salt of the acetyl washed with dilute acetic 
acid is completely hydrolyzed. When prepared in this way, however, 
its melting point is found to be 152°. When this material is dissolved 
in alcohol and added to boiling dilute sulfuric acid, the acetyl separates 
in closed-ring form, and the melting point is 238°. This suggests 
that in the sodium salt the acetyl exists in open-ring form, and hydro- 
lysis of the sodium from the molecule leaves the open-ring structure. 
This is further corroborated by analysis of the silver salt. 

Preparation of the silver salt of the acetyl. — If the acetyl is dis- 
solved in alcohol and then make alkaline with sodium hydroxid and 
the alcohol evaporated, the addition of ammonia and silver nitrate 
produces no precipitate. This is also true of thyroxin in the open- 
ring form. If 50 mg. of the acetyl are dissolved in 2 to 3 c.c. of alcohol, 
to which are added 2 to 3 c.c. of pyridin and 10 c.c. of water, and the 
alcohol is removed by boiling, the addition of silver nitrate to the 
aqueous pyridin solution of thyroxin will cause a precipitate to form. 
This is not crystalline in nature, although under some conditions 
it may be possible to separate it in crystal form. The silver salt 
may be filtered on a Buchner funnel and washed with water without 
decomposition. 

5.14 mg. of the silver salt of the acetyl contained 2.S6 mg. of iodin - 44.06 
per cent. 

Calculated for Ag 2 CnHi 2 0eNl3 iodin = 44.35 per cent. 
" AgCi a HnO«NIi =51.91 " " 



Digitized by VjOOQLC 



THE CHEMICAL IDENTIFICATION OP THYROXIN 481 

The iodin content of the silver salt of the acetyl indicates the 
addition of 2 per cent too much silver for the di-silver salt of the open 
ring form of the acetyl, and 220 per cent too much silver for the 
mono-salt of the closed-ring form. These results, proving conclusively 
that not one but two atoms of silver had added to the acetyl, show that 
in an alkaline solution the acetyl exists in open-ring form. 

The open-ring structure of the acetyl is also indicated by the in- 
creased solubility of the acetyl in weak bases such as pyridin, quino- 
lin, and very dilute ammonia. The terminal carboxyl in thyroxin 
is so weak that the acetyl derivative would not be soluble in these 
reagents in the closed-ring form. 

Preparation of the ureid. — Only pure thyroxin should be used in 
preparation of the ureid for the same reasons given under the prepa- 
ration of the acetyl. One hundred milligrams of di-s odium or zinc 
salt of thyroxin are added to 10 to 15 c.c. of glacial acetic acid contain- 
ing 200 mg. of potassium cyanate. Solution of the salt of thyroxin 
should be completed as the ureid is soluble in acetic acid. Five cubic 
centimeters of water, 5 c.c. of alcohol, and 5 c.c. of 50 per cent sulfuric 
acid are added and the alcohol, water, and acetic acid are removed 
under diminished pressure, the same as in the preparation of the 
acetyl. The sulfate of the ureid is dissolved in 15 c.c. of alcohol, fil- 
tered, and slowly added to a beaker containing 200 c.c. of water and 5 
c.c. of 50 per cent sulfuric acid, which is heated to boiling. The ureid 
separates in crystal rosettes or needles. 

Sample 1. 4.78 mg. of ureid contained 2.91 mg. of iodin = 69.81 per cent. 

" St. 5.04 " " " " 3.07 " " " - 61.03 " " 

" 3. 5.03 " " " " 3.05 " " " - 60.74 " " 

Calculated for CitHuOsNiIi = 60.67 per cent. 

Preparation of the methyl ester. — One hundred milligrams of the 
silver salt of thyroxin are suspended in 20 c.c. of alcohol to which are 
added 4 to 5 c.c. of methyl iodid. The crystals are occasionally 
stirred and allowed to stand at a temperature of 40° to 50° for several 
hours until decomposition of the silver salt is complete. This "is 
indicated by separation of silver iodid in voluminous form. The 
silver iodid is removed by filtration. If the alcohol is allowed to 
evaporate, the dimethyl derivative crystallizes in the form of fine 
threads. They may be separated by formation of the sulfate similar 
to the preparation of the acetyl. Five cubic centimeters of water and 

'19—31 



Digitized by VjOOQLC 



482 E. C. KENDALL AND A. E. OSTERBERG 

5 c.c. of 50 per cent sulfuric acid are added to the alcohol filtrate from 
the silver iodid and the alcohol is removed by distillation under 
diminished pressure. The dimethyl derivative separates probably as 
the sulfate. It is insoluble in water, but soluble in alcohol. Treat- 
ment with alcoholic sodium hydroxid frees the carboxyl group, and 
the monomethyl derivative is then slightly soluble in aqueous sodium 
hydroxid. The methyl ester is very difficultly purified and has 
not been prepared containing a theoretical percentage of iodin. It 
appears to retain silver iodid even after repeated precipitation. 

The action of nitrous acid on thyroxin. — Twenty-five milligrams of 
thyroxin dissolved in 2 c.c. of dilute sodium hydroxid were added 
to the de-aminizing chamber of the Van Slyke apparatus, and the 
usual procedure was followed, shaking for three minutes; 0.69 c.c. of 
nitrogen was evolved. The apparatus was allowed to stand nine 
minutes and was again shaken for three minutes; 0.06 c.c. of nitrogen 
was obtained. Four minutes later it was again shaken for three 
minutes and 0.04 c.c. was obtained. The total, liberated in twenty- 
two minutes, showed 1.72 per cent amino nitrogen which is 72 per cent 
of the total nitrogen contained in the molecule. 

Another 25 mg. sample of thyroxin, after three minutes' shaking, 
liberated 0.75 c.c. of nitrogen. This is equivalent to 1.60 per cent of 
amino nitrogen in the molecule and is 67 per cent of the total nitrogen. 

Twenty-five milligrams of the amino carboxyl salt form of thyroxin 
suspended in 2 c.c. after three minutes shaking gave 0.08 c.c. ten min- 
utes later; after three minutes more shaking, 0.06 c.c; and ten min- 
utes later, after three minutes shaking, 0.04 c.c. ; total amount liberated 
= 0.18 c.c. which is equivalent to 0.093 mg. of amino nitrogen, and is 
16 per cent of the total nitrogen. Ten milligrams of keto form of 
thyroxin suspended in 2 c.c. of water gave no amino nitrogen. 

The amino nitrogen in 25 mg. of the acetyl was determined as 
described above. After three minutes 0.11 c.c, and after ten and one- 
half minutes, 0.11 c.c more of nitrogen was liberated. The nitrogen 
in the amino form amounted to 24 per cent of the total nitrogen in 
the molecule. 

The nitrogen in isatin and indol, given off as amino-nitrogen, 
was determined. One hundred milligrams of isatin after four minutes 
gave 1.72 c.c and after five minutes more gave 0.41 c.c. of nitrogen. 
This volume was equivalent to 1.13 mg. of nitrogen and amounted to 
12 per cent of the total nitrogen present. One hundred milligrams of 



Digitized by VjOOQLC 



THE CHEMICAL IDENTIFICATION OF THYROXIN 483 

indol gave 1.27 c.c. after three minutes, and 0.34 c.c. of nitrogen after 
four minutes more shaking. This is equivalent to 0.86 mg. and is 
7 per cent of the total nitrogen in indol. 

Beside the action of nitrous acid on thyroxin, liberating some of 
the nitrogen as amino nitrogen, a characteristic color reaction is pro- 
duced. A few milligrams of pure thyroxin, added to 5 c.c. of alcohol 
containing three to four drops of 50 per cent hydrochloric acid to 
which are added five to six drops of 1 per cent sodium nitrite solution, 
will develop a yellow color. This is increased by boiling. If the solu- 
tion is cooled and concentrated ammonia is added until distinctly alka- 
line, a pink color is obtained. This is a sensitive reaction for thyroxin* 
a color being produced by one part of thyroxin in 40,000 part.- 
solution. If acetic or sulfuric acid is substituted for hydrochloric, 
the yellow color is not so deep and the addition of ammonia does not 
produce a pink color but gives a yellowish orange color. If the sample 
of thyroxin is impure, a yellow instead of a pink color is produced with 
ammonia. The acetyl and ureid derivatives give the same reaction, 
producing a pink color with ammonia. 

The pine-splinter reaction for indol. — From 15 to 20 mg. of 
thyroxin are placed in a test-tube with 5 c.c. of 30 per cent sodium 
hydroxid and sufficient water to carry the thyroxin into solution. As 
the excess of water is boiled off, thyroxin will precipitate as a di-sodium 
salt, but on further heating, after the water has been almost com- 
pletely driven off and the temperature of the solution has been raised 
to between 100° and 200°, the di-sodium salt is again dissolved and a 
faint indol-like odor is given off. A pine-splinter moistened with 
hydrochloric acid is turned red by the vapors given off from the fusion. 

The effect of thyroxin on polarized light. — One gram of thyroxin 
was dissolved in 20 c.c. of alcohol and 7 c.c. of water containing 300 mg. 
of sodium hydroxid. The solution was filtered and placed in a 2 dm. 
tube and its effect on polarized light* was determined. No rotation of 
light could be determined. The solution of thyroxin was then placed 
in a 1 dm. tube. Under these conditions there was no measurable 
rotation of light. 

The effect of hydrazine on thyroxin. — If thyroxin is added to 
hydrazin hydrate, it immediately dissolves. If water is added, 
thyroxin remains in solution. The addition of carbon dioxid pre- 
cipitates thyroxin as the amino carbonate. If the solution of thyroxin 
in the hydrazin hydrate is boiled after the addition of water, thyroxin 



Digitized by VjOOQLC 



484 



E. C. KENDALL AND A. E. OSTERBERG 



precipitates as from aramoniacal solution. No condensation with 
hydrazin, phenylhydrazin, semicarbazone, or hydroxylamin could 
be demonstrated when thyroxin was dissolved in alkaline alcohol to 
which these reagents were added, in acid alcohol to which these 
reagents were added, together with sodium carbonate or pyridin, or 
when dissolved in pyridin to which the reagents were added. Either 
decomposed products due to heating at too high temperature or un- 
changed thyroxin were recovered. 

The melting points of thyroxin and its derivatives. — The following 
melting points of thyroxin in its several forms and its derivatives are 
recorded to illustrate the agreement between different samples (Tables 
1 to 9). It is evident that among some of the derivatives fairly large 
variations occur, but between any two different forms the differences 
are much greater than that found between the melting points of two 
samples of the same derivatives. 

The following salts of thyroxin and its derivatives were not melted 
when heated to 260°: di-sodium and mono-sodium salt of thyroxin; 
di-potassium and mono-potassium salt of thyroxin; barium salt of 
thyroxin; di-silver salt of thyroxin; di-sodium salt of acetyl; di- 
silver salt of acetyl; calcium salt of acetyl. 

» 
Table 1. — The Melting Point of the Keto Form of Thyroxin 



No. of sample 


1 Slight 
| browning 


Sublime or ' First 
| mist > droplets 


Completely 
melted 


Froth 


125 


1 




248 


250 


250 


32 


• 




241 


248 


248.9 


123 


i 




235 


247 


247 


124 


i 


240 


246 


246 


81 




| 243 


245 


246 


91 


! 


241 


242 


243 


107 


■ 


241 


242 


242 


115 






239 


242 


242 


119 






239 


241 


241.5 


117 






237 


241 


241 


97 




| 236 


240 


241 


" 28 






195 


240 


241.5 


80 






239 


240 


240 


59 






238 


239 


240.5 


51 






236 


239 


240 



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THE CHEMICAL IDENTIFICATION OF THYROXIN 



485 



Table 2. — The Melting Point of the Enol Form of Thyroxin 



No. of sa*mple 


Slight 
browning 


Sublime or 
mist 


First 
droplets 


Completely 
melted 


Froth 


40 


190 




200 


202 


205 


41 


180 




200 


205 


205 


42 


190 




200 


204.5 


204.5 


43 


160 


190 


200 


204 


204 


44 


160 


190 


202 


208 


208 


46 


170 


190 


200 


202 


204 


49 


165 


190 


203 


206 


206 


50 


165 




196 


201 


201 


53 


150 




198 


203 


204 


55 


160 


190 


200 


202 


204 


108 


160 




198 


204 


205 


109 


180 


198 


206 


208 


208 


110 


170 




200 


202 


203 


111 








203 


205 



Table 3. — The Melting Point of the Amino Hydrate Form 



No. of sample » h ^g^ 


Sublime or 
mist 


First I Completely i i?,^4k 
droplets 1 melted Froth 


129 

114 

i 




1 1 
214 | 216 | 216.5 

207 | 212 1 214 



Table 4. — The Melting Point of the Amino Carboxyl Salt Form 



No. of sample 


Slight 
browning 


Sublime or 
mist 


First 
droplets 


Completely 
melted 


Froth 


86 


215 


219 


220 


221 


88 


i 


216 


218 


221 


89 




216 


218 


219 


95 




i 219.5 


221 


222 


100 




222 


223.5 


223.5 


105 




1 222 


223 


223.5 


112 




! 216 


220 


221 


113 






217 


221 


222 


118 






221 


222 


222.5 


120 






221 


224 


224 


121 






222 


224 


225 


127 






218 


222 


223 


130 








225.5 


226 



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486 



E. C. KENDALL AND A. E. OSTERBERG 



Table 5. — The Melting Point op Acid Salts op the Amino Group 



I No. of 
I sample 



Slight 
browning 



Sublime 
or mist 



First 
droplets 



Com- 
pletely 
melted 



Froth 



Amino sulfate 


83 

93 

103 

104 


1 

182 207 

162 ! 202 

180 | 206 

180 1 206 


208 
204 
207 
207 


208.5 


tt *< 


204 


tt it 


208 


Amino oxalate 


208 


Amino formate 


101 






202 


205 


208 


<< it 


76 


150 




190 


205 


206.5 


tt a 


84 




180 


202 


204 


204 


a tt 


82 


160 ( 


204 


205 


Amino acetate 


102 


1 202 


205 


208 


Amino carbonate 


87 


160 I i 204 


206 


206 



Table 6. — The Melting Point of the Acetyl 



No. of sample 



Slight 
browning 



Sublime or 
mist 



First 
droplets 



Completely 
melted 



Froth 



34 




1 

220 


228 


290 


30 






225 


235 


236 


29 






215 


223 


232 



Table 7. — The Melting Point of *the Sulfate of the Acetyl 



No. of sample 



I 



Slight 
browning 



Sublime or 
mist 



First 
droplets 



Completely 
melted 



Froth 



27 
25 
24 



111 



100 



150 
122 
106 



200 
190 
150 



Table 8. — The Melting Point of the Acetyl in Open-ring Form 



No. of sample 



Slight 
browning 



Sublime or 
mist 



First 
droplets 



Completely 
melted 



Froth 



8 
35 
11 



150 
146 



160 
155 
152 



174 
155 
216 



Table 9. — The Melting Point of the Ureid 



No. 



Slight 



of sample | h ™W g 



21 



Sublime or l First 

mist I droplets 



Completely 
melted 

225 



Froth 



225 



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THE CHEMICAL IDENTIFICATION OF THYROXIN 487 

SUMMARY 

The most important physical and chemical properties of thyroxin 
may be summarized as follows: 

1. Thyroxin is a colorless, odorless, crystalline substance, insoluble 
in aqueous solutions of all acids, including carbonic. It is soluble in 
sodium, ammonium, and potassium hydroxids, and is very slightly 
soluble in sodium and potassium carbonate. Besides forming salts 
with metals, thyroxin also forms salts with acids. 

2. The iodin content of thyroxin and the iodin content of the 
sulfate salt were found to be 65 and 60 per cent respectively. This 
established the molecular weight of 585. Ultimate analysis and a 
study of the derivatives of thyroxin show the structural formula to be 
4, 5, 6 tri-hydro-4, 5, 6 tri-iodo-2 oxy-beta-indol propionic acid. 

3. In the presence of alkali metal hydroxids, thyroxin forms 
di-basic salts through the carboxyl and hydroxy groups. In the 
presence of carbonates, thyroxin forms mono-basic salts with the 
carboxyl group alone. The imino group forms salts with mineral 
and formic acids but not with acetic. The salts of mineral acids are 
soluble in alcohol, but no acid salt of thyroxin is appreciably soluble 
in water. Thyroxin forms derivatives through the amino nitrogen, 
such as the acetyl and ureid, and through its carboxyl and hydroxy 
groups, such as the di-methyl derivative. 

4. Thyroxin exists in four distinct forms: (1) The keto form with 
the imino carbonyl groups, melting point 250°; (2) the enol form in 
which the hydrogen migrates from the imino to the carbonyl forming 
the hydroxy group, melting point 204°; (3) an open-ring form in which 
the elements of water enter the molecule between the imino and car- 
bonyl groups forming an open-ring structure with amino and car- 
boxyl groups, which exist in salt formation, called the amino carboxyl 
salt form, melting point 225°; and (4) a tautomeric form of this in 
which the elements of water add to the nitrogen, making the amino 
hydrate form, melting point 216°. If an acid is added to an enol form 
of thyroxin, the ring opens and the acid forms an amino-acid salt. 
The reason why weak organic acids including carbonic can add to 
the nitrogen of thyroxin-forming amino salts is that the ring is un- 
stable in neutral aqueous solutions and the nitrogen tends to exist 
iD the pentad state, adding either the elements of water and forming an 
amino hydrate, or adding a carboxyl and forming an amino salt. 



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488 E. C. KENDALL AND A. E. OSTERBERG 

These reactions could occur only with a strongly basic group. The 
amino group of anilin and the imino group of indol or isatin are too 
feebly basic to react the same as thyroxin with weak organic acids. 

5. Thyroxin is not easily oxidized or reduced, but will yield to both 
oxidation and reduction if sufficiently strong agents are used. 

6. In alkaline solutions the iodin is broken off from the thyroxin 
molecule, not as free iodin, but as hypo-iodous acid. This reaction 
is accelerated by sunlight. Sunlight also produces pink color com- 
pounds from the colorless thyroxin molecule. 

BIBLIOGRAPHY 

1. Ciamician, G. and Silber, P.: Ueber die Constitution der riechenden Bestand- 
theile des Sellerieols, Ber. d. deutsch. chem. Gesellsch., 1897, xxx, 1419. 

2. Kendall, £. C: The isolation in crystalline form of the compound containing 
iodin, which occurs in the thyroid, Jour. Am. Med. Assn., 1915, lxiv, 2042. 



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THE BASAL METABOLIC RATE IN EXOPHTHALMIC 

GOITER WITH A BRIEF DESCRIPTION OF THE 

TECHNIC USED AT THE MAYO CLINIC* 

IRENE SANDIFORD 



"In each mammal there is a basal metabolism." 19 By the term 
"basal metabolism" or better, "basal metabolic rate," of an organism 
is meant the minimal heat production of that organism, measured 
from twelve to eighteen hours after the ingestion of food and with the 
organism at complete muscular rest. This minimal heat production 
may be determined directly by actual measurement by means of a 
calorimeter, or indirectly, by calculating the heat production from an 
analysis of the end products which result from oxidation within the 
organism, or specifically, from the amount of oxygen used and the 
corresponding amount of carbon dioxid produced, together with the 
total nitrogen eliminated in the urine (although, for clinical work, the 
urinary nitrogen may be neglected). 

The experimental work of Lavoisier 17 marks the beginning of 
researches on metabolism and to him belongs the conception that 
the life processes are those of oxidation with the elimination of heat. 
Technically, the problem was beset with many difficulties for it was 
necessary not only to measure the amount of heat lost by radiation 
and conduction from the body (direct calorimetry), but also to collect 
accurately the various end products resulting from combustion within 
the body, from which data the heat production can be calculated 
(indirect calorimetry), in order to prove from a comparison of the 
results obtained from the two methods that the law of conservation 
of energy also holds for the living organism. Furthermore, before 
the method of indirect calorimetry could be employed the heat values 
of carbohydrate, fat, and protein had also to be determined in order 
to calculate the heat derived from their combustion in the body. The 
solution of these problems was greatly advanced by Carl Voit 28 and 

* Reprinted from Endocrinology, 1920, iv, 71-87. 
489 



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490 IRENE SANDIFORD 

his pupils, the chief of whom were Pettenkofer 22 and Rubner. 27 The 
heat values of carbohydrate and fat were readily determined by 
Rubner 25 since these two substances are oxidized to the same end 
products (carbon dioxid and water) whether burning in the body or in 
a calorimeter. In the case of protein, however, the problem was 
somewhat more difficult for a part of the end products of protein 
combustion in the body is eliminated in the urine and feces and the 
latent heat thereby lost had to be subtracted from the heat value 
of protein as determined in the calorimeter. 

In 1894 Rubner 26 constructed the first successful respiration 
calorimeter designed for the measurement of the gaseous exchange 
between a living organism and the atmosphere which surrounds it 
and the simultaneous measurement of the quantity of heat produced 
by that organism. By means of this apparatus Rubner verified the 
method of Pettenkofer and" Voit of calculating the heat production 
(indirect calorimetry) and he proved that the law of conservation 
of energy held for the living organism. 

It was not until 1905 that the respiration calorimeter was brought 
to a high degree of technical perfection by Atwater and Benedict. 1 
With their apparatus it was possible to determine simultaneously 
with the measurement of the heat elimination, not only the carbon 
dioxid production, but also the oxygen consumption of the subject. 
Studies made by Benedict and his associates, at the Carnegie Nutrition 
Laboratory, using the perfected calorimeter, have added greatly to 
the exactness of our knowledge with regard to the metabolism in 
prolonged fasting, 4 the metabolism of normal persons, 6 of infants, 8 
and of diabetics. 7 They also confirmed the agreement between direct 
and indirect calorimetry. Lusk 18 and Du Bois and their co-workers 
have likewise demonstrated, in a large series of pathologic conditions, 
the close agreement between the two methods. As a result of these 
investigations the use of such a complicated apparatus as the respira- 
tion calorimeter has been shown to be unnecessary for clinical work 
and that in its place the comparatively simple method of indirect 
calorimetry may be used. 

Krogh, 16 of Copenhagen, and Carpenter, 11 of the Carnegie Nutrition 
Laboratory, have described and compared in great detail the various 
kinds of respiration apparatus used in indirect calorimetry. Carpenter 
has shown that for indirect determinations two types of apparatus 
are suitable, the closed circuit and the gasometer. 



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BASAL METABOLIC RATE IN EXOPHTHALMIC GOITER 491 

By far the best apparatus of the closed circuit type is the Benedict 
unit apparatus. 2 By means of a mask, mouth piece or nasal tubes, 
the subject rebreathes air from a closed system in which the carbon 
dioxid is absorbed by soda lime, and, as the oxygen is used up, it is 
replaced by oxygen in known amounts. The air within the apparatus 
is kept in constant circulation by means of a blower. A small spirom- 
eter is inserted in the circuit as an expansion chamber and volumetric- 
ally records the respiratory movements on a smoked drum. Know- 
ing the weights of oxygen used and the carbon dioxid eliminated, 
one can readily calculate the heat production. As pointed out by 
Carpenter, this apparatus is very satisfactory and indeed the best 
for many purposes, especially when used in conjunction with a calor- 
imeter or with the cot-chamber calorimeter described by Benedict 
and Tompkins. 9 We have found, however, that for clinical work 
the unit apparatus is rather cumbersome. It requires constant check- 
ing to see that it is absolutely air tight, for a leak of 20 or 30 c.c. dur- 
ing a fifteen minute determination will appreciably affect the result, 
because such a leak in this type of apparatus will be equivalent to the 
loss of so much oxygen and not equivalent to the loss of so much air 
as is the case in the gasometer method. Furthermore, the accumula- 
tion errors of the apparatus fall on the oxygen and not on the carbon 
dioxid^ determination, thus causing an error in the calculation of the 
respiratory quotient and heat production. The absorbing chemicals 
must be changed frequently and with the repairing and constant 
checking of the apparatus it is on the whole difficult to use in clinical 
work, particularly if many determinations are to be made. 

The portable respiration apparatus recently devised by Benedict 5 
for clinical work is a modification of his unit apparatus described 
above. It is designed primarily to give a rapid and at the same time 
a comparatively accurate measurement of the oxygen consumption 
without involving analyses or weighing. We have not adopted it 
as we prefer to determine not only the oxygen consumption, but also 
the carbon dioxid elimination since the heat production can thereby 
be more accurately calculated. Moreover, the difficulties inherent 
in the closed circuit type of apparatus are still present in the portable 
apparatus. 

For clinical work the gasometer method introduced by Tissot 29 in 
1904 is considered by us the most satisfactory. Briefly, the determina- 
tions are made in the following manner: A mask is adjusted over the 



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492 



IRENE SANDIFORD 



patient's mouth and nose and by means of expiratory and inspiratory 
valves the total volume of the patient's expired air is collected in a 
gasometer for a known period of approximately ten minutes. Dupli- 
cate determinations are made of the carbon dioxid and oxygen content 
of the expired air, the analyses being done in the Haldane gas analysis 



b. 




Fiq. 229. — Mask and connections showing valves and intake pipe. 

apparatus. 14 Since the ventilation rate for each minute is known 
as well as the amount the carbon dioxid produced, and the oxygen 
absorbed, it is possible to calculate by means of calorie tables the 
total calories produced each hour. 

The following points in the routine determination of the basal 
metabolic rate deserve further discussion: To obtain comparable 
results the patient must be in the postabsorptive condition, that is, 



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BASAL METABOLIC RATE IN EXOPHTHALMIC GOITER 493 

he must fast for at least twelve hours preceding the test. It is very 
important that this rule should be observed because all kinds of foods 
cause an increase in the heat production and this effect may not 
entirely disappear for twelve hours after their ingestion. 28 Moreover, 
the patient must be at complete rest and the effects of previous muscular 
exertion eliminated by requiring him to rest in bed for twenty min- 
utes before the test is started for we have shown in a series of experi- 
ments that a test period of this length of time is quite sufficient to 
obtain the basal metabolism. 11 During the preliminary rest period 
an observer sits with the patient, noting at intervals the character 
and rate of the heart beat and the respiration; likewise, about the 
middle of the period, the blood pressures, both systolic and diastolic, 
are obtained. After twenty minutes' rest a mask is accurately 
adjusted over the nose and mouth of the patient and securely held in 
place by means of tapes so that there is no leakage of air around the 
mask (Fig. 229). A mask is preferable to either a mouthpiece or nasal 
tubes. With a little experience it is possible to adjust the mask so 
that it is not only comfortable for the patient, but also air-tight. 
One of the chief advantages of the gasometer method is that should a 
very slight leak of a few cubic centimeters occur around the mask 
during the course of an experiment the end result is not appreciably 
affected, while a leak of a similar volume in the closed circuit apparatus 
has a value at least five times as great, because in the latter case it is 
equivalent to the loss or gain of so much pure oxygen. 

During the test proper the observer sits with the patient recording 
his pulse and respiration rates and noting and recording on a special 
chart any movements. Care is taken to impress the patient that even 
slight movements materially affect the test and it is almost always 
possible to obtain their complete co-operation. Sometimes, however, 
in an extremely nervous person, a basal rate cannot be obtained on the 
first test. Instead of repeating the determination the same day the 
patient is instructed to return the following morning for a second test. 
In such instances the rate will occasionally be ten points lower than 
that obtained the first time when the patient was unduly nervous and 
frightened about an unknown procedure. 

The total volume of the expired air is collected in a gasometer 
(Fig. 230) over a known length of time. Unlike the work with the 
closed circuit apparatus no appreciable error is introduced by failing 
either to start or stop the experimental period at exactly the end of a 



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494 IRENE SANDIFORD 

normal respiration, a difficult thing to do with accuracy in the case of 
patients who breathe irregularly. Samples of the expired air are then 
collected over mercury in sampling tubes and analyzed in duplicate for 
carbon dioxid and oxygen. Approximately 10 c.c. of expired air are 




Fig. 230. — Movable gasometer. 

transferred into the burette of the Haldane gas analysis apparatus 
(Fig. 231) and after adjusting certain levels the reading of the initial 
volume of the sample is made, reading to the nearest 0.001 c.c. The 
gas sample is then passed back and forth over a solution of dilute 
potash to absorb the carbon dioxid. The levels of the solution are 
again adjusted and a second reading of the volume of the remaining 



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BASAL METABOLIC RATE IN EXOPHTHALMIC GOITER 



495 



gas in the burette made. The contraction in volume of the gas, due 
to the absorption of the carbon dioxid by the potash solution, divided 
by the original volume, gives the percentage of carbon dioxid in the 
expired air. In like manner the percentage of oxygen is determined, 
potassium pyrogallate solution being used as the absorbent for oxygen. 
The gasometer method is particularly suitable for clinical work 
because each step in the procedure can be checked by a second assist- 




Fio. 231. — Haldane gas analysis apparatus. 

ant, reducing to a minimum the chance of technical errors. Although 
the method requires care and accuracy in every part of the procedure, 
it is possible to teach the technic to laboratory workers who have had 
no preliminary scientific training other than that obtained in a high 
school. The most difficult step in the procedure is the analysis of the 
expired air. This, however, we have found to be inconsiderable. Our 
assistants can obtain routinely duplicate analyses agreeing [within 
0.04 per cent for carbon dioxid and 0.06 per cent for oxygen, and they 



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496 IRENE SANDIFORD 

are able also to take entire care of their gas analysis apparatus. The 
equipment necessary for this method is simple and inexpensive and 
when properly constructed is rarely out of order and, except for clean- 
ing, requires very little mechanical care. Furthermore, the apparatus 
is free from the many mechanical difficulties inevitably inherent in a 
closed circuit system in which the air current is driven by an electric 
pump. In the metabolism laboratory at the Mayo Clinic we are 
averaging 30 cases a day and have developed a very definite and routire 
procedure which has decreased the chance of technical error to less than 
1 per cent.* 

The calculation of the basal metabolic rate from the experimental 
data is very simple. Knowing the volume of air expired by the patient 
in a minute (the ventilation rate) and the percentage of carbon dioxid 
and oxygen in the expired air it is possible to calculate the volume of 
oxygen absorbed by the patient in one hour, as well as the correspond- 
ing amount of carbon dioxid produced. Since the respiratory quotient, 
that is, the ratio between the volume of carbon dioxid produced and the 
volume of oxygen absorbed, indicates the kind of food being burned at 
the time of the determination, and since by means of calorie tables the 
calorific value of one liter of oxygen absorbed by the body in the 
burning of these substances is known, the total heat production each 
hour can be calculated readily. The total number of calories must 
be divided by the surface area, a factor dependent on the patient's 
height and weight. The number of calories for each square meter of 
body surface each hour must then be compared with the normal 
standards of comparison which are dependent on the age and sex of the 
patient. For convenience basal metabolic rates are expressed in 
percentages of the normal and when the heat production is greater 
than the normal the percentage is plus, and when less than normal the 
percentage is minus. 

A very important contribution was made by Du Bois 12,18 in deter- 
mining the heat production in normal controls. Rubner 24 had sug- 
gested that the heat production of an individual is proportional to 
his surface area. For the determination of the surface area Meeh 21 
proposed the formula: Surface area (in square centimeters) — 12.3 (a 
constant) X weight in grams. . However, using the surface area 

* The details of the technic are described in a laboratory manual by Boothby 
and Sandiford. The apparatus may be obtained from H. N. Elmer, 1136 Monadnock 
Building, Chicago. 



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BASAL METABOLIC RATE IN EXOPHTHALMIC GOITER 497 

obtained by this formula as a basis of comparison, the heat production 
of normal controls still showed quite wide variations, although not 
so great as when compared on the basis of weight alone. By exact 
measurements of the surface area of several bodies Du Bois demon- 
strated an error in the above formula due in greater part to the fact 
that the height of the subject was neglected. As a result of further 
studies Eugene F. Du Bois and Delafield Du Bois 12 ' 18 devised a form- 
ula based on height and weight by means of which the surface area 
can be calculated with an average error of 1.7 per cent. This form- 
ula is: 

A = W <M25 X H 0725 X 71 g 4 

where A is the surface area in square centimeters, W is the weight in 
kilograms and H is the height in centimeters, and 71.84 is a constant. 
On the basis of this formula they then constructed a height-weight 
chart by means of which the surface area can be estimated at a glance. 
Du Bois 12,13 , using this new height-weight chart for the determination 
of the surface area in conjunction with his standards of normal basal 
metabolism with regard to age and sex, further showed that the meta- 
bolism of normal persons can be predicted with an accuracy of ± 10 
per cent. This fact has been confirmed both by Means 20 and by 
Boothby 19 . Benedict 3 has severely criticized the method of predicting 
the heat production from the unit of surface area, maintaining ' that 
the metabolism or heat output of the human body, even at rest , does 
not depend on Newton's law of cooling and, therefore, is not propor- 
tional to the body surface." Harris and Benedict 16 in a very exhaus- 
tive treatise have reconsidered the entire problem of the prediction 
of the normal basal metabolic rate and show that by proper biometric 
formulas based on stature, body weight, and age (the same factors used 
by Du Bois), " results as good as or better than those obtainable from 
the constant of basal metabolism per square meter of body surface 
can be obtained by biometric formulas involving no assumption con- 
cerning the derivation of surface area but based on direct physical 
measurements." Since their publication there has not been sufficient 
time to study in detail the fundamental accuracy of the two methods of 
prediction; we have, however, tabulated 404 determinations of the 
basal metabolic rate expressed in percentages above and below normal, 
using both the standards of Du Bois and of Harris and Benedict. 
The average rates of all the cases show that the rates obtained by 

•19—32 



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498 IRENE SANDIFORD 

Harris and Benedict's method are 6.5 points higher than those obtained 
by Du Bois' method. The parallelism between the results obtained 
by the two methods is strikingly shown by the fact that 195 of the 404 
determinations are within ±2.5 of the average variation. Only 
52 of the entire 404 rates deviate more than 7.5 from the average 
variation. The comparative agreement, therefore, of the two methods 
is very satisfactory, indicating as it does the similarity of both methods 
of comparison, and supporting in a high percentage of the cases the 
clinical conclusions based on the Du Bois and Du Bois height- weight 
chart and the Du Bois normal standards for comparison. 

The metabolism laboratory at the Mayo Clinic was opened in 
March, 1917, by Boothby and Sandiford, under the clinical direction 
of Dr. H. S. Plummer, and in that year 1143 metabolic rates were 
determined on 549 patients. At that time the number of cases that 
could be studied in the laboratory in proportion to the number of 
thyroid cases at the clinic was relatively small. In consequence, 
considerable care was taken by Dr. Plummer to select typical cases 
of the various groups of thyroid disorders, and with his permission 
this analysis of the metabolic rates in the cases of exophthalmic goiter 
studied during 1917 is presented. 

The determination of the basal metabolic rate is of the greatest 
value in thyroid disorders because it gives a very accurate mathemat- 
ical index of the degree of functional activity of the thyroid gland. 
For example, in exophthalmic goiter the metabolic rate may rise well 
over 100 per cent above normal while in myxedema, with apparently 
complete cessation of thyroid activity, the rate falls to the region of 
40 per cent below normal. In the milder cases of both groups the 
metabolic rate variations from the normal are proportionately smaller. 
On the other hand, beside thyroid disorders, there are no diseases that 
have so far been shown to have a constant and distinct variation from 
the normal in the basal metabolic rate except disorders of the pitui- 
tary gland, conditions of profound inanition, and fevers. However, an 
occasional case is met with in which there is a variation in the basal 
metabolic rate that cannot be explained or properly classified. Such 
variations are most frequent in patients with considerable nephrits or 
anemia. No definite instance of an increased basal metabolic rate has 
been found in that group of cases known as neurasthenia or chronic 
nervous exhaustion. The basal metabolic rate has proved, therefore, 
to be of great value in the differential diagnosis of neurosis simulating 
hyperthyroidism and true hyperthyroidism. 



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BASAL METABOLIC RATE IN EXOPHTHALMIC GOITER 499 

In 182 cases of exophthalmic goiter before any treatment was in- 
stituted the average metabolic rate was +51 per cent with an average 
pulse rate of 115. In 13 patients whose average metabolic rate, as 
outpatients, was +59 per cent with an average pulse rate of 115 the 
average metabolic rate fell to +46 per cent and the average pulse rate 
to 108 as a result of approximately one week's complete rest in bed. 
In 5 patients whose average metabolic rate, determined within two to 
five days after they entered the hospital, was +59 per cent and the 
pulse 118, after a further rest in bed of approximately one week's 
duration there was a definite improvement in their condition, as shown 
by a fall in the metabolic rate to an average of +48 per cent and 
pulse to 104. 

The effect of a single ligation was studied in 16 cases. The basal 
metabolic rate taken after the patient had had several days' rest 
in bed and within five days before the first ligation was +54 per cent 
and the pulse 116. One week after the single ligation the average 
metabolic rate had decreased to +44 per cent and the pulse to 112. 

The immediate result of any operative procedure in hyperthyroid- 
ism is to cause at first a rise in the metabolic rate for a few days, fol- 
lowed by a gradual fall to a distinctly lower average on the level than 
that obtained preceding the operation. The curve of the basal meta- 
bolic rate on the average roughly parallels the pulse rate curve. The 
former is, however, a far more accurate index of the degree of hyper- 
thyroidism than is the pulse rate, as the latter shows more individual 
and extraneous variations, for example, the irregularities of auricu- 
lar fibrillation. 

The effect of the second ligation is likewise a general im- 
provement in the patient's condition as evidenced by a decrease in the 
metabolic rate. An average figure of any value on the immediate 
result of the second ligation in the patients in the 1917 series cannot 
be given as practically no rates were obtained in the same case imme- 
diately preceding and following the second ligation. There is a very 
marked improvement in these patients when they return for their 
thyroidectomy two to four months after the second ligation. In 22 
patients (Table 1) there was an average decrease in the basal metabolic 
rate from +46 per cent to +39 per cent and in the pulse from 115 to 
107 with a gain in weight from 46. 4 to 54.5 kg. in the determina- 
tions made a few days after the second ligation as compared with the 
data obtained after three months' rest at home and just previous to 



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500 IRENE SANDIFORD 

thyroidectomy. From the clinical history it is probable that the basal 
metabolic rate determined at the time the patients returned for 
operation after having had two ligations and three months 9 rest at 
home may not necessarily represent in all cases the period of maximum 
improvement produced by the two ligations and rest. A definite im- 
provement from thyroidectomy in those patients who had had two 
ligations and a three months' rest was shown two weeks following 
operation by a decrease in the basal metabolic rate from +39 per 
cent to +16 per cent and in the pulse rate from 107 to 89. 

In another group of 19 patients (Table 2) with exophthalmic goiter 
in whom the preliminary basal metabolic rate varied between +13 per 
cent and +50 per cent, giving an average of +31 per cent with an 
average pulse rate of 104, and in whom a primary thyroidectomy 
was done without any other preliminary treatment, except for a short 
rest in bed, the basal metabolic rate fell, about two weeks after opera- 
tion, to +5 per cent and the pulse to 84. 

The general effect of the treatment adopted at the Mayo Clinic 
for severe cases of exophthalmic goiter may be illustrated, then, by 
the following data: In a group of 22 patients (Table 1) the average 
basal metabolic rate, before any treatment was instituted, was +66 
per cent with a pulse rate of 123. As a result of rest in bed and 
two ligations the rate in these patients before they went home had 
decreased to +46 per cent and the pulse to 115. The further im- 
provement that occurred from three months' rest at home reduced 
the average metabolic rate to +39 per cent and the pulse rate to 107, 
and finally, after thyroidectomy and just before the patients were 
discharged from the clinic, the rate was + 16 per cent and the pulse 89. 

As will be noted following thyroidectomy there is almost always a 
marked decrease in the basal metabolic rate within two weeks after 
the operation and, as a rule, there is still further improvement in the 
succeeding months, just as is seen to occur in the interval after the 
second ligation. Occasionally, a varying degree of hyperthyroidism 
may persist, as shown by an elevated basal metabolic rate. In these 
cases a second (and rarely a third) thyroidectomy is indicated. 



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BASAL METABOLIC RATE IN EXOPHTHALMIC GOITER 



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502 



IRENE SANDIFORD 



Table 2. — The Effect of Primary Thyroidectomy on the Basal Metabolic 
Rate in Exophthalmic Goiter 



Case 



21458J 
196806 
202992 
200219 
201229 
202481 
202527 
194686 
212298 
2022S2 
203326 
3396 
198725 
196664 
203291 
199740 
217150 
215895 
208637 

Average . 



I Preliminary 

I 



before treatment About two w $£ after °W 



Pulse 



104 



I 



B. M. R., 



| per cent 



Pulse 



B. M. R.. 

per cent. 



88 


4-50 ! 


70 


+ 19 


109 


i 4-45 


93 


+ 3 


107 


4-45 


92 


+ 5 


145 


4-42 . 


115 


+ 12 


102 


4-40 


75 


+ 14 


105 


, 4-39 


68 


+ * 


112 


1 4-36 


92 


+ 15 


97 


+35 


75 


+ 1 


108 


4-34 


91 


+ 5 


113 


+32 


118 


+32 


127 


+30 


89 


+ 10 


101 


1 +29 


83 


+ 13 


99 


+27 


67 





79 


+21 


58 


-11 


87 


+ 18 


73 


- 6 


95 


+18 ' 


69 


- 7 


99 


1 +16 


85 


- 5 


118 


+ 16 


98 


- 9 


89 


+13 


84 


+ 6 



+31 



84 



+ 5 



BIBLIOGRAPHY 

1. At water, W. O. and Benedict, F. G.: A respiration calorimeter with appliances 
for the direct determination of oxygen. Carnegie Inst, Washington, 1905, Pub. No. 
42, 1905. 

2. Benedict, F. G.: Ein Universalrespirationsapparat. Deutsch. Arch. f. klin. 
Med., 1912, cvii, 156. 

3. Benedict, F. G.: Factors affecting basal metabolism. Jour. Biol. Chem., 1915, 
xx, 263-313. 

4. Benedict, F. G.: A study of prolonged fasting. Carnegie Inst, Washington, 
1915, Pub. No. 203. 

5. Benedict, F. G.: A portable respiration apparatus for clinical use. Boston Med. 
and Surg. Jour., 1918, clxxviii, 567. 

6. Benedict, F. G. and Carpenter, T. M.: Metabolism and energy transformation 
of healthy man during rest Carnegie Inst, Washington, 1910, Pub. No. 126. 

7. Benedict, F. G. and Joslin, £. L.: Metabolism in diabetes mellitus. Carnegie 
Inst, Washington, 1910, Pub. No. 136. A study of metabolism in severe diabetes. 
Carnegie Inst, Washington, 1912, Pub. No. 176. 



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BASAL METABOLIC RATE IN EXOPHTHALMIC GOITER 503 

8. Benedict, F. G. and Talbot, F. B. : The gaseous metabolism of infants. Car- 
negie Inst., Washington, 1914, Pub. No. 201. The physiology of the new-born infant. 
Carnegie Inst., Washington, 1914, Pub. No. 238. 

9. Benedict, F. G. and Tompkins, Edna H.: Respiratory exchange, with a descrip- 
tion of a respiration apparatus for clinical use. Boston Med. and Surg. Jour., 1916, 
clxxiv, 857. 

10. Boothby, W. M. and Sandiford, Irene: Technic of basal metabolic rate de- 
terminations. Philadelphia, Saunders, 1920. 

11. Carpenter, T. M.: A Comparison of methods for determining the respiratory 
exchange of man. Carnegie Inst., Washington, 1915, Pub. No. 216. 

12. DuBois, D. and DuBois, E. F.: The measurement of the surface area of man. 
Clinical calorimetry. Paper V. Arch. Int. Med., 1915, xv, 868-881. 

13. DuBois, D. and DuBois, E. F.: A formula to estimate the approximate surface 
area if height and weight be known. Clinical calorimetry. Paper X. Arch. Int. 
Med., 1916, Xvii, 863-871. 

14. Haldane, J. S.: Methods of air analysis. London, Griffin, 1912. 

15. Harris, J. A. and Benedict, F. G.: A biometric study of basal metabolism in 
man. Carnegie Inst, Washington, 1919, Pub. No. 279. 

16. Krogh, A.: The respiratory exchange of animals and man. (With excellent 
bibliography.) London, Longmans, Green & Co., 1916, 181 pp. 

17. Lavoisier, A. L. and Laplace: Memoire sur la chaleur. Mem. de math, et de 
phys. de T Acad. d. Sc., 1780, 355. 

Lavoisier, A. L. and Seguin: Premier memoire sur la respiration des animaux. 
Mem. de math, et de phys. de l'Acad. d. Sc., 1789, 566. (Also: "Oeuvres de 
Lavoisier," 1862.) 

18. Lusk, G.: A series of papers on clinical calorimetry by Lusk and his associates 
appearing in The Archives of Internal Medical beginning in 1915, xv. 

19. Lusk, G.: Science of nutrition. 3 ed., Philadelphia, Saunders, 1917, 641 pp. 

20. Means, J. H. : Basal metabolism and body surface. A contribution to the nor- 
mal data. Jour. Biol. Chera., 1915, xxi, 263-268. 

21. Meeh, K.: Oberflachenmessungen des menschlichen Korpers. Ztschr. f. Biol , 
1879, xv, 425-458. 

22. Pettenkoffer, M.: Ueber die Respiration. Ann. d. Chem. u. Pharm., 1862, ii, 
Suppl. 1. 

23. Pettenkoffer, M. and Voit, C. : Untersuchungen tiber die Respiration. Ann. d. 
Chem. u. Pharm., 1862, Suppl. 52. 

24. Rubner, M.: Ueber den Einfluss der Korpergrosse auf Stoff und Kraftwechsel. 
Ztschr. f. Biol., 1883, xix, 535-562. 

25. Rubner, M.: Calorimetrische Untersuchungen. Ztschr. f. Biol., 1885, xxi, 
250-334. 

26. Rubner, M.: Die Quelle der tierischen Warme. (Comparison of direct and 
indirect calorimetry.) Ztschr. f. Biol., 1894, xxx, 73. 

27. Rubner, M.: Die Gesetze des Energieverbrauchs bei der Ernahrung. Leipzig, 
Deuticke, 1902, 426 pp. 

28. Soderstrom, G. F., Barr, D. P. and DuBois, E. F.: The effect of a small break- 
fast on heat production. Clinical calorimetry. Paper XXVI. Arch. Int. Med., 1918, 
xxi, 613-620. 

29. Tissot, J. : Nouvelle meihode de mesure et d'inscription du d6bit et des mouve- 
ments respiratoires de l'homme et des animaux. Jour, de phys. et de path, gen., 1904, 
vi,688. 



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TUBERCULOSIS OF THE THYROID* 

W. A. PLUMMER AND A. C. BRODERS 



The literature on tuberculosis of the thyroid may be divided into 
three classes: (1) Reports of isolated cases usually of the so-called pri- 
mary type, in a number of which- the clinical picture and pathologic 
appearance of the gland had been modified by secondary infection and 
abscess formation; (2) descriptions of the histologic findings in thyroids 
obtained in routine necropsies in persons having died of general miliary 
tuberculosis; and (3) studies based on reviews of the pathology of 
simple and exophthalmic goiters. 

Reports such as those of Fraenkel in which tuberculosis of the thy- 
roid was said to have been demonstrated in all except six of 580 necrop- 
sies following deaths from general miliary tuberculosis are of value, but 
clinicians are especially interested in reports based on pathologic 
material from persons who have had definite goiters or who have com- 
plained of symptoms due directly or indirectly to thyroid disease. 

Ruppanner, in 1908, reported 3 cases of colloid goiter in which he 
had demonstrated areas of tubeiculosis. von Werdt, in 1911, found 
tuberculosis in one gland in 28 cases of exophthalmic goiter, and in 
three glands in 444 cases of simple goiter. Mosiman, in 1917, re- 
viewed the literature and reported 9 cases in which operation had been 
performed in the Crile Clinic. The glands in 5 cases which had been 
previously diagnosed exophthalmic goiter also showed hyperplasia. 
In the goiter of one of 2 patients who had been designated as having 
had mild or questionable exophthalmic goiter were hyperplastic areas; 
one patient who had had hypertension, and another, sarcoma of the 
thyroid did not show hyperplasia. 

Mosiman's admirable report brought out the striking relationship 
between hyperthyroidism and tuberculosis of the thyroid. This asso- 
ciation is evidently not a coincidence; either a hypertrophic gland is 
rendered more susceptible to invasion by the tuberculosis bacillus or 

* Presented before the Minnesota State Medical Association, Minneapolis, 
October, 1919. 

Reprinted from Minn. Med., 1920, iii, 279-288. 

504 



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TUBERCULOSIS OF THE THYROID 505 

the infection stimulates the parenchyma to an abnormal activity and 
is thus indirectly responsible for the hyperthyroidism with its attend- 
ant symptoms. Although the great majority of hypertrophic thy- 
roids are not tuberculous, any infection which may even in a few 
instances be an etiologic factor is of interest in dealing with a disease 
the cause of which is so shrouded in mystery. 

Few, if any, of the cases of tuberculosis of the thyroid which have 
been reported were diagnosed previous to the microscopic examination 
of the glands. The condition was not suspected in any of our cases 
previous to operation, and their study was pursued in the hope that 
some evidence might be gained which would indicate whether or not 
the hypertrophy was secondary to the tuberculous infection, and also 
with a view to determining, if possible, any diagnostic points which in 
the future might lead us at least to suspect the condition previous to 
or at the time of operation. In using the term hypertrophy we refer 
to the cell hypertrophy, that is, the transition of the normal cuboidal 
to the columnar type of epithelial cell. 

We shall report briefly 7 cases that have been under observation in 
the Mayo Clinic. A full discussion of the symptoms and findings will 
not come within the limits of this paper. For convenience these cases 
are divided into three groups: (1) Cases with high degree of hyper- 
thyroidism, (2) cases with a moderate degree of hyperthyroidism, and 
(3) cases in which hyperthyroidism was mild or absent. 

Case 1 (Group 1). — This patient had had general symptoms for 
four years, but no local symptoms. The thyroid gland was diffusely 
enlarged and slightly nodular, but not unusually hard. There was no 
tenderness to pressure. Bruits and thrills were present. The basal 
metabolic rate was +48. A clinical diagnosis was made of exoph- 
thalmic goiter, with the degree of severity 3 on a scale of 1 to 4. At 
operation the gland was thought to be hypertrophic with multiple 
adenomas. The pathologic examination revealed scattered areas of 
tuberculosis, a slight amount of fibrosis, some round cell infiltration, 
and extensive parenchymatous hypertrophy. 

Case 2 (Group 1). — This patient had been conscious of the goiter 
for eight months; symptoms had been noted for ten months. The 
basal metabolic rate was +87. The thyroid gland was slightly en- 
larged with the granular "feel" of a hypertrophic condition. Bruits 
and thrills were present. The clinical diagnosis was exophthalmic 
goiter, degree of severity 3. At operation both lobes were found to 



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506 W. A. PLUMMER AND A. C. BRODERS 

be about two and one-half times normal in size and had the appearance 
of an ordinary hypertrophic gland. The pathologic findings were the 
same as those in Case 1. 

Case 1 (Group 2). — The goiter had been diagnosed by the family 
physician six months before. General symptoms had been noted for 
two years; there were no local symptoms. The thyroid gland was 
about normal in size; it had no nodules but was unusually hard for a 
hypertrophic gland. The basal metabolic rate was +26. Exoph- 
thalmic goiter was diagnosed, the degree of severity 2. A normal 
sized gland which appeared to be hypertrophic was found at operation. 
Extensive tuberculosis, a moderate amount of fibrosis and round cell 
infiltration, and a fair degree of parenchymatous hypertrophy were 
found on pathologic examination. 

Case 1 (Group 3). — The general symptoms in this case had been 
present for one year; no thyroid enlargement and no local symptoms 
had been noted. The patient's neck was short and fleshy, and, except 
for a hard nodule on the left side about 1.2 or 1.8 cm: in diameter, 
neither lobe of the thyroid could be palpated. The isthmus was 
palpable and unusually hard. The basal metabolic rate was +21. 
The diagnosis was definite hyperthyroidism, with degree of severity 
1. The condition was considered unusual and thought to be exo- 
phthalmic goiter or thyrotoxic adenoma. The gland was found 
firmly adherent to all the surrounding structures, muscles, fascia, and 
trachea. Very little bleeding occurred during the removal of the gland 
which indicated an old ipflammatory condition. In cutting across the 
gland the surgeon found a large amount of scar tissue. The pathol- 
ogist reported extensive tuberculosis, marked fibrosis, round cell 
infiltration, slight parenchymatous hypertrophy, and great destruction 
of the gland. 

Case 2 (Group 3). — Four months before this patient's examination 
enlargement of the right lobe had been noticed. General symptoms 
had probably existed for one year; there were no local symptoms. The 
thyroid had the contour of a normal gland, although about three times 
its normal size; it was hard, and slightly nodular. The basal meta- 
bolic rate was +21. A tentative diagnosis was made of mild hyper- 
thyroidism, with degree of severity 1, probably exophthalmic goiter, 
possibly carcinoma of the thyroid. At operation the gland was found 
to be hard and resembled carcinoma, but was believed to be some form 
of infection throughout the gland. As in Case 1 of Group 3, the patho- 



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TUBERCULOSIS OF THE THYROID 507 

logic examination revealed extensive tuberculosis, marked fibrosis, 
round cell infiltration, slight parenchymatous hypertrophy, and ex- 
tensive destruction of the gland. 

Case 3 (Group 3). — The general symptoms had probably been pres- 
ent for two years. The patient complained of pressure in the throat. 
A very hard tumor in the left lobe of the thyroid was not sensitive to 
pressure; no bruits were heard in the thyroid vessels. The meta- 
bolic rate was not determined. A diagnosis was made of neurasthenia 
with a possible thyrotoxicosis from an adenoma. Because of the den- 
sity of the tumor, carcinoma of the thyroid was also considered. 
Examination of the gland removed at operation showed degeneration 
and inflammation. The only normal tissue remaining was that in 
the pyramidal lobe. The surgeons were suspicious of malignancy. 
The pathologist discovered about the same amount of tuberculous 
destruction as in Cases 1 and 2 of this group, but more parenchymatous 
hypertrophy. 

Case 4 (Group 3). In this case enlargement of the right lobe of 
the thyroid had been noticed for one month. Three weeks before 
examination the left side had begun to enlarge. A neurasthenic 
syndrome had been present for years. The lobes were not greatly 
enlarged, but were very hard; a small nodule could be palpated in 
each. A clinical diagnosis was made of a small adenoma of the thyroid, 
possibly carcinoma, because of the recent developments and extreme 
hardness of the gland. At operation a small hard tumor pressing on 
the trachea was found. The surgeons were unable to exclude malig- 
nancy, but considered the condition inflammatory. The pathologic 
findings were practically the same as in the other cases in Group 3, 
although there was more destruction and fibrosis, and no parenchy- 
matous hypertrophy. 

The 2 cases in Group 1 represent typical high grade exophthalmic 
goiteis. Before operation the glands were believed to be ordinary 
hypertrophic thyroids. The surgeon did not detect any unusual con- 
dition. The pathologist reported extensive parenchymatous hyper- 
trophy with tuberculosis in scattered areas. 

The single case in Group 2 represents an intermediate stage. 
This was a case of typical exophthalmic goiter, but with a less severe 
degree of hyperthyroidism. The surgeon apparently did not consider 
it more than an ordinary hypertrophic gland. The pathologist 



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508 W. A. PLUMMER AND A. C. BRODERS 

reported a fair degree of parenchymatous hypertrophy, also very 
extensive tuberculous involvement. 

In all but one of the cases in Group 3 the thyroids were smaller 
than those in Group 1 . The glands were hard, somewhat fixed, and nod- 
ular; two of them had grown rapidly. The clinician had recognized 
an unusual condition in all, and had suspected carcinoma in three. 
In the first 2 cases the definite evidence of a mild degree of hyper- 
thyroidism was confirmed by basal metabolic rates. The last 2 
patients were examined before we had the means of estimating the 
basal metabolism; however, hyperthyroidism had been suspected in 
the first of these; in the last case no mention was made of the possibility 
of hyperthyroidism. The parenchyma of the gland was so completely 
destroyed that the diagnosis of the absence of hyperthyroidism made 
at that time was probably correct. The striking point in the cases 
is that 5 of the patients, probably 6, were suffering from hyperthy- 
roidism. The greater the tuberculous involvement the less severe 
the toxic symptoms. This may be explained by the more extensive 
destruction of the gland. 

In 2 of the 5 patients with definite hyperthyroidism the goiter 
was noticed before the symptoms; in 2 the opposite was true, and in 
one no thyroid enlargement had been discovered. In these findings 
there is nothing decisive to indicate that tuberculosis preceded the 
hyperthyroidism. Even had we had a larger series it is doubtful 
whether definite conclusions could have been reached, as such tuber- 
culous processes would undoubtedly have been progressing for months 
before the enlargements could have been noticed. The symptom in 
these cases are so insidious that the time of the onset of the condition 
is difficult to determine. Probably all cases of tuberculosis of the 
thyroid are secondary to some process elsewhere in the body. In 
this series if such foci were present they were too small to have any 
clinical significance; evidence of active tuberculosis elsewhere in the 
body could not be demonstrated on critical examination. 

In Case 2 of Group 3 definite evidence of myxedema appeared at 
the end of two months. This condition has also been noticed in 
cases of simple chronic thyroiditis following operations. It is ques- 
tionable whether the usual amount of thyroid tissue should be extirpated 
when the gland is inflammatory because of the possibility of a resulting 
hypothyroidism caused by the subsequent destruction of the remaining 



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TUBERCULOSIS OF THE THYROID 509 

parenchyma. Cases of the type placed in Group 1 cannot be dis- 
tinguished from ordinary exophthalmic goiter. 

In cases similar to those placed in Group 3, the condition may at 
least be suspected before operation. Carcinoma of the thyroid may be 
associated with hyperthyroidism, but the growth is usually more 
nodular and is not so apt to involve the entire gland without causing 
a much larger tumor. Chronic simple thyroiditis may give the same 
thyroid signs as tuberculosis, but in our experience it has not been 
associated with hyperthyroidism. Sarcoma of the thyroid is a rare 
condition, and we have never had a case of actinomycosis. 

Three of our patients were operated on too recently to give us any 
definite information as to the ultimate prognosis following operation 
but they have all been benefited. One patient had myxedema. 
One is in perfect health two years following operation. The other 
2 have not been heard from recently. 

BIBLIOGRAPHY 

1. Fraeokel, E.: Ueber Schildrusentuberculose. Arch. f. path. Anat., 1880, civ, 
58-72. 

2. Mosiman, R. E.: Tuberculosis of the thyroid. Surg., Gynec. and Obst , 1917, 
xxiv, 680-693. 

S. Ruppanner, E.: Ueber tuberkulose Strumen, ein Beitrag zur Kenntnis der 
Schildrusentuberkulose. Frankf. Ztschr. f. Path., 1908-19099, ii, 513-547. 

4, v. Werdt, F.: Ueber Lymphfollikelbildung in; Strumen. Frankf. Ztschr. f. 
Path., 1911, vii, 401-444. 



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THE SELECTION OF OPERATION FOR EXOPH- 
THALMIC GOITER* 

W. E. SISTRUNK 

Surgery, at the present time, gives a higher percentage of cures 
than any other measure in the treatment of exophthalmic goiter. For 
a number of years the mortality following surgical procedures has 
gradually decreased, largely because much has been learned regarding 
the selection of the type of operation which is safest in any given case, 
and because the greater number of patients are operated on earlier 
in the course of the disease than formerly, and at a time when they are 
better surgical risks. It is possible by present day methods to operate 
in large number of consecutive case of exophthalmic goiter without a 
death. There are, however, a few patients who fail to respond to 
pre-operative medical treatment and who must be subjected to opera- 
tion at a relatively high risk in order to offer a chance for cure. Re- 
fusal to operate in this group of cases naturally diminishes the death 
rate. On the other hand, poor judgment in selecting the type of 
operation which is best and safest in a given case, and in advising 
operation in certain cases that are non-surgical at the time, increases 
the mortality. 

If the disease is left to run a normal course it progresses in several 
different ways. In a few instances the onset is sudden, with rapid 
development of symptoms, and the progress is so quick that the patient 
soon becomes a poor surgical risk. In the greater proportion of 
patients, however, the onset of the disease is so gradual that in its 
incipiency it can scarcely be recognized save by one highly experi- 
enced in the diagnosis of hyperthyroidism. In such patients the symp- 
toms gradually increase in number and severity and an enlargement 
the thyroid gland occurs. As a rule the disease reaches its height dur- 
ing the second six months of its course and the patient passes through 
a period which usually is referred to as a crisis. During such periods 
all the symptoms become markedly exaggerated; the pulse rate is 

♦Reprinted from Jour. Am. Med. Assn., 1920, Ixxiv, 306-308. 
510 



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OPERATION FOR EXOPHTHALMIC GOITER 511 

high, there is rapid emaciation and weight loss with extreme nervous- 
ness and mental irritability, and oftentimes vomiting and diarrhea; 
marked damage occurs to the vital organs, such as the heart, liver and 
kidneys. Unless the disease proves fatal, the majority of patients 
improve greatly after a period of from one to several weeks, although 
as a rule they are never so well after having passed through a crisis 
as they were before. The amelioration of symptoms may persist 
for a period varying from a few months to several years, but in the 
majority of patients a second or even a third crisis eventually develops. 
With each crisis the damage to vital organs, especially the heart, 
liver, and kidneys increases, until the patient finally suffers more from 
the symptoms produced by these degenerative changes than from the 
disease itself. In a third but small group of patients the disease runs 
a chronic course from its onset, without the development of acute 
crises. 

Fortunately and unfortunately patients improve when treated medi- 
cally; fortunately, because patients unfit for surgical treatment may 
improve to such an extent that they become fairly good surgical risks; 
and unfortuntely, because a knowledge of the fact that improvement 
occurs under medical treatment leads many practitioners to use med- 
ical measures only in the management of exophthalmic goiter, appar- 
ently without fully realizing the sad state to which a large percentage 
of the patients thus treated will ultimately be reduced. Many patients 
who have been treated medically for a long period apply for surgical 
aid and are found to have such marked degenerative changes in their 
vital organs that it is impossible for .surgery to effect a cure. Opera- 
tion usually stops the progress of the disease even in this stage, but 
the damage to the vital organs cannot be repaired; it would be quite as 
reasonable to expect to cure patients with well pronounced central 
nervous system lesions from tertiary syphilis by means of anti-syphil- 
itic treatment. 

It is often a perplexing problem to decide just how toxic a given 
patient is and how much damage has been produced by the disease, 
and for these reasons it is difficult to decide what operative procedures 
the patient will safely endure. Although the mortality is largely 
affected by the decision, no absolute rules can be given as to the selec- 
tion of the best type qf operation; each case must be judged on its 
own merits. A condition which in one patient would justify the per- 
formance of a thyroidectomy, in another patient would be counter- 



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512 W. E. SISTRUNK 

balanced by some other factor that would make the operation dan- 
gerous. There seems to be no way of elucidating all the possible con- 
ditions that may arise, as these can be recognized only by observers 
who are highly experienced in dealing with patients with exophthalmic 
goiter. 

In operating in such cases in the Mayo Clinic certain factors are 
taken into consideration in selecting the type of operation. The ideal 
surgical procedure in exophthalmic goiter is partial thyroidectomy as 
soon as the first symptoms of the disease appear and it can be definitely 
proved, by metabolic tests, that hyperthryoidism is present. At 
this stage of the disease a primary thyroidectomy can usually be per- 
formed with a very low death rate, and many such patients are re- 
stored to normal health. The percentage of patients operated on 
during the early stage of the disease is steadily increasing, and an 
increase in the percentage of cures will result. 

It cannot be denied that certain patients improve and apparently 
recover under medical treatment. However, in the beginning of the 
disease it is impossible to distinguish between the patients who may 
fall in this group and those who are destined to become severely dam- 
aged as the disease progresses. A great responsibility is assumed, 
therefore, by advising medical treatment in early cases, in which thy- 
roidectomy might prevent the severe conditions, and in many instances 
the death of patients who would fail to improve under medical 
treatment. 

The metabolic rate is a definite index to the degrees of hyper- 
thyroidism in a given patient at a given time. It is of very great 
value as a diagnostic aid in the early stages of exophthalmic goiter 
when studied in conjunction with the symptoms and general appear- 
ance of the patient. As a rule, the clinical picture presented by the 
patient, the metabolic rate, and the pulse pressure run hand in hand, 
the symptoms increasing and decreasing as the metabolic rate varies. 
However, patients do not always present the same clinical picture 
while carrying similar metabolic rates; for instance, one patient with 
a rate of +50 per cent may be extremely sick and in a crisis, while 
another with the same rate may show a very different clinical picture 
and be a fair surgical risk. Some persons seem to develop a certain 
tolerance to increased metabolism. We occasionally see a patient 
who, while carrying a certain metabolic rate, must be classified as a bad 
surgical risk. Later, this same patient, while carrying the same rate, 



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OPERATION FOR EXOPHTHALMIC GOITER 513 

may present a different clinical picture and stand the operation which 
previously was considered unsafe. In all instances in which a high 
metabolic rate is associated with symptoms indicative of a high 
grade toxemia, such as nervousness, irritability, cardiac dilatation, 
high pulse rate, loss of weight and strength, nausea, vomiting and 
diarrhea, the condition must be looked on as serious and non-surgical. 
The metabolic rate gives no indication of the amount of damage which 
may have been done previously; it can be used only partially as a 
means of deciding on the best type of operation to perform. We 
make a careful selection of the type of operation for patients with a 
rate above +40 per cent, and we hesitate to perform a primary 
thyroidectomy in patients with metabolic rates 60 to 70 per cent above 
normal. In the majority of such patients without marked cardiac 
damage, and who except for this high rate would seem good risks, 
we perform a preliminary ligation as a means of testing the ability 
of the patient to stand any operative procedure without the precipita- 
tion of an acute hyperthyroidism. If a mild reaction follows the 
ligation, a thyroidectomy is performed after seven or eight days, but 
if the reaction is severe, it is best to do a second ligation and to wait 
three or four months before performing a thyroidectomy. 

Certain patients, after having had the disease for some months, 
present themselves for treatment because of increased symptoms. As 
a rule they have lost weight and probably are losing weight at the time. 
Such patients will usually be found to have high metabolic rates. If 
the loss of weight and general strength has been marked, and especi- 
ally if the patients are highly nervous and irritable, we have found 
that a thyroidectomy is performed with considerable risk in these 
cases because a crisis may be precipitated by even a slight surgical 
procedure. In such instances we usually perform two superior polar 
ligations, under local anesthesia, at one operation or at intervals of 
seven or eight days, and wait for three or four months before perform- 
ing a thyroidectomy. 

Patients who consult us during acute crises are considered ex- 
tremely dangerous surgical risks, and we prefer to treat them by means 
of rest, fluids, and careful nursing until the crisis is passed, and there 
is a gain in weight, with a corresponding subsidence of the pulse rate, 
the nervousness, and mental irritability. The metabolic rate usually 
drops considerably following a crisis; therefore, patients who have 
just passed such a period are not likely to be thrown into an acute 

'19—33 



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514 W. E. SISTRUNK 

hyperthyroidism